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    Expression of the irisin precursor FNDC5 in skeletal muscle correlates with aerobic exercise performance in patients with heart failure. Lecker Stewart H,Zavin Alexandra,Cao Peirang,Arena Ross,Allsup Kelly,Daniels Karla M,Joseph Jacob,Schulze P Christian,Forman Daniel E Circulation. Heart failure BACKGROUND:Exercise-induced increase in peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression has been shown to increase the expression of the fibronectin type III domain containing 5 (FNDC5) gene and thereby its product, irisin, in mice. Given that exercise intolerance is a hallmark characteristic of heart failure (HF), and because PGC-1α and irisin promote exercise benefits in animals, we hypothesized that expression of these genes relates to aerobic performance in patients with HF. METHODS AND RESULTS:Systolic HF (left ventricular ejection fraction ≤40%) patients underwent cardiopulmonary exercise testing to evaluate aerobic performance. High versus low aerobic performance was assessed using oxygen consumption (peak Vo(2) [>14 versus ≤14 mL O(2)·kg(-1)·min(-1)]) and ventilatory efficiency (VE/Vco(2) slope [<34 versus ≥34]). Muscle biopsies of the vastus lateralis and real-time polymerase chain reaction were used to quantify muscle gene expression. Twenty-four patients were studied. FNDC5 (5.7±3.5 versus 3.1±1.2, P<0.05) and PGC-1α (9.9±5.9 versus 4.5±1.9, P<0.01) gene expressions were greater in the high-peak Vo(2) group; correlation between FNDC5 and PGC-1α was significant (r=0.56, P<0.05) only in the high-peak Vo(2) group. Similarly, FNDC5 and PGC-1α gene expression was greater in the high-performance group based on lower VE/Vco(2) slopes (5.8±3.6 versus 3.3±1.4, P<0.05 and 9.7±6 versus 5.3±3.4, P<0.05); FNDC5 also correlated with PGC-1α (r=0.55, P<0.05) only in the low VE/Vco(2) slope group. CONCLUSIONS:This is the first study to show that FNDC5 expression relates to functional capacity in a human HF population. Lower FNDC5 expression may underlie reduced aerobic performance in HF patients. 10.1161/CIRCHEARTFAILURE.112.969543
    Can Pre-analytical Mistake Bearing Irisin Concentrations Be an Indicator of Coronary Artery Disease? Aydin Suna Korean circulation journal 10.4070/kcj.2017.0060
    Adropin and Irisin in Patients with Cardiac Cachexia. Mansur Alfredo José Arquivos brasileiros de cardiologia 10.5935/abc.20180109
    Serum irisin levels, precocious myocardial infarction, and healthy exceptional longevity. Emanuele Enzo,Minoretti Piercarlo,Pareja-Galeano Helios,Sanchis-Gomar Fabian,Garatachea Nuria,Lucia Alejandro The American journal of medicine BACKGROUND:Skeletal muscles produce irisin. Growing controversy exists on the association between this myokine and chronic disease risk. On the basis of the potential protective effects that irisin could exert on both vascular function and skeletal muscle mass, we hypothesized that an elevated level of this molecule may contribute to successful aging. METHODS:Serum irisin levels were measured using enzyme-linked immunosorbent assay in disease-free centenarians, young healthy controls, and patients with precocious acute myocardial infarction. RESULTS:We found the highest levels of serum irisin in disease-free centenarians (35.3 ± 5.5 ng/mL) compared with young healthy controls (20.7 ± 6.3 ng/mL) and especially with young patients with acute myocardial infarction (15.1 ± 5.4 ng/mL). CONCLUSIONS:Our study demonstrates that healthy centenarians are characterized by increased serum irisin levels, whereas levels of this molecule were found to be significantly lower in young patients with myocardial infarction. Our findings may prompt further research into the role played by irisin not only in vascular disorders but also in life span modulation. 10.1016/j.amjmed.2014.04.025
    Irisin attenuates angiotensin II-induced cardiac fibrosis via Nrf2 mediated inhibition of ROS/ TGFβ1/Smad2/3 signaling axis. Chen Rui-Rui,Fan Xue-Hui,Chen Gang,Zeng Guang-Wei,Xue Yu-Gang,Liu Xiong-Tao,Wang Chi-Yao Chemico-biological interactions Angiotensin II-related cardiac fibrosis is one of the key pathological changes of the hypertrophied left ventricle in various heart disease. Irisin was recently reported to confer cardio-protective and anti-oxidative effects, while whether it can reverse the renin-angiotensin-aldosterone system(RAAS) activation related(angiotensin II-induced) cardiac fibrosis is unknown. In this study, we found that angiotensin II-induced cardiac dysfunction and fibrotic responses were dampened by irisin treatment in mice. Mechanistically, angiotensin II induced robust ROS generation, which in turn triggered activation of pro-fibrotic TGFβ1-Smad2/3 signaling and subsequent collagen synthesis and fibroblast-myofibroblast transformation in cardiac fibroblasts. In contrast, Irisin treatment suppressed angiotensin II-induced ROS generation, TGFβ1 activation, collagen synthesis and fibroblast-myofibroblast transformation, the effects of which was accompanied by Nrf2 activation and also abolished by a Nrf2 targeted siRNA. Taken together, we here identified irisin as a promising anti-fibrotic therapeutic for angiotensin II-related cardiac fibrosis. 10.1016/j.cbi.2019.01.031
    Irisin: a potentially candidate marker for myocardial infarction. Kuloglu Tuncay,Aydin Suna,Eren Mehmet Nesimi,Yilmaz Musa,Sahin Ibrahim,Kalayci Mehmet,Sarman Emine,Kaya Nalan,Yilmaz Osman Fatih,Turk Ahmet,Aydin Yalcin,Yalcin Mehmet Hanifi,Uras Nimet,Gurel Ali,Ilhan Selcuk,Gul Evrim,Aydin Suleyman Peptides Myocardial infarction (MI) causes energy depletion through imbalance between coronary blood supply and myocardial demand. Irisin produced by the heart reduces ATP production by increasing heat generation. Energy depletion affects irisin concentration in circulation and cardiac tissues, suggesting an association with MI. We examined: (1) irisin expression immunohistochemically in rat heart, skeletal muscle, kidney and liver in isoproterenol (ISO)-induced MI, and (2) serum irisin concentration by ELISA. Rats were randomly allocated into 6 groups (n=6), (i) control, (ii) ISO (1h), (iii) ISO (2h), (iv) ISO (4h), (v) ISO (6h), and (vi) ISO (24h), 200mg ISO in each case. Rats were decapitated and the blood and tissues collected for irisin analysis. Blood was centrifuged at 1792 g for 5 min. Tissues were washed with saline and fixed in 10% formalin for histology. Serum irisin levels gradually decreased from 1h to 24h in MI rats compared with controls, the minimum being at 2h, increasing again after 6h. Cardiac muscle cells, glomerular, peritubular renal cortical interstitial cells, hepatocytes and liver sinusoidal cells and perimysium, endomysium and nucleoi of skeletal muscle were irisin positive, but its synthesis decreased 1-4h after MI. At all time-points, irisin increased near myocardial connective tissue, with production in skeletal muscle, liver and kidney recovering after 6h, although slower than controls. Unique insight into the pathogenesis of MI is shown, and the gradually decrease of serum irisin might be a diagnostic marker for MI. 10.1016/j.peptides.2014.02.008
    Central and peripheral irisin differentially regulate blood pressure. Zhang Weizhen,Chang Lin,Zhang Chao,Zhang Ruthann,Li Ziru,Chai Biaoxin,Li Jiyao,Chen Eugene,Mulholland Michael Cardiovascular drugs and therapy INTRODUCTION:Irisin is a newly identified 112 amino acid hormone, derived as a product of fibronectin type III domain containing 5 (FNDC5), which is highly related to metabolic activity in skeletal muscle and brown fat. The effects of irisin on cardiovascular functions are unknown. PURPOSE:To explore the effects of central and peripheral irisin on cardiovascular functions. METHODS:Irisin was either administrated into 3rd ventricle of rats or intravenously, and its effects on blood pressure and cardiac contractibility measured. RESULTS:Administration of recombinant human irisin into the 3rd brain ventricle of rats activated neurons in the paraventricular nuclei of the hypothalamus. Central administration of irisin increased blood pressure and cardiac contractibility. Exogenous irisin reversed atenolol-induced inhibition of cardiac contractibility. In contrast, peripheral administration of irisin reduced blood pressure in both control and spontaneously hypertensive rats. Irisin dilated mesenteric artery rings through ATP-sensitive potassium channels. CONCLUSION:Our studies indicate that central and peripheral irisin may differentially regulate cardiovascular activities. 10.1007/s10557-015-6580-y
    Circulating irisin levels and coronary heart disease: association with future acute coronary syndrome and major adverse cardiovascular events. Aronis K N,Moreno M,Polyzos S A,Moreno-Navarrete J M,Ricart W,Delgado E,de la Hera J,Sahin-Efe A,Chamberland J P,Berman R,Spiro A,Vokonas P,Fernández-Real J M,Mantzoros C S International journal of obesity (2005) INTRODUCTION:Irisin is a newly discovered myokine, associated with 'browning' of the white adipose tissue, obesity, insulin resistance and metabolic syndrome. The purpose of this study is to evaluate circulating irisin as a predictor of acute coronary syndromes (ACSs) and major adverse cardiovascular events (MACE). METHODS:Sub-study 1: a case-control study, nested within the Veteran's Affairs Normative Ageing Study, evaluating circulating irisin levels in 88 ACS cases and 158 age- and sampling year-matched controls, as a predictor of ACS. Sub-study 2: a prospective cohort study, where 103 participants with established coronary artery disease were stratified by circulating irisin levels at the time they received percutaneous coronary interventions (PCIs) and were followed for the development of MACE. RESULTS:Study 1: there was no association between irisin levels and ACS in otherwise healthy individuals (odds ratio: 1.00 95% confidence interval: (0.99-1.00)). Study 2: the incidence of MACE was significantly lower in the first irisin tertile compared with the second and third (incidence rate 0 vs 0.92 (0.51-1.61) vs 0.57 (0.28-1.14) events per 1000 person-days; P < 0.01). This was primarily driven by the lower incidence of unstable angina (incidence rate 0 vs 0.61 (0.31-1.22) vs 0.43 (0.19-0.96) per 1000 person-days; P = 0.01). CONCLUSION:This is the first study to date that demonstrates that, although circulating irisin levels do not predict the development of ACS in healthy individuals, increased irisin levels are associated with the development of MACE in patients with established coronary artery disease after PCI. 10.1038/ijo.2014.101
    Irisin Controls Growth, Intracellular Ca2+ Signals, and Mitochondrial Thermogenesis in Cardiomyoblasts. Xie Chao,Zhang Yuan,Tran Tran D N,Wang Hai,Li Shiwu,George Eva Vertes,Zhuang Haoyang,Zhang Peilan,Kandel Avi,Lai Yimu,Tang Dongqi,Reeves Westley H,Cheng Henrique,Ding Yousong,Yang Li-Jun PloS one Exercise offers short-term and long-term health benefits, including an increased metabolic rate and energy expenditure in myocardium. The newly-discovered exercise-induced myokine, irisin, stimulates conversion of white into brown adipocytes as well as increased mitochondrial biogenesis and energy expenditure. Remarkably, irisin is highly expressed in myocardium, but its physiological effects in the heart are unknown. The objective of this work is to investigate irisin's potential multifaceted effects on cardiomyoblasts and myocardium. For this purpose, H9C2 cells were treated with recombinant irisin produced in yeast cells (r-irisin) and in HEK293 cells (hr-irisin) for examining its effects on cell proliferation by MTT [3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and on gene transcription profiles by qRT-PCR. R-irisin and hr-irisin both inhibited cell proliferation and activated genes related to cardiomyocyte metabolic function and differentiation, including myocardin, follistatin, smooth muscle actin, and nuclear respiratory factor-1. Signal transduction pathways affected by r-irisin in H9C2 cells and C57BL/6 mice were examined by detecting phosphorylation of PI3K-AKT, p38, ERK or STAT3. We also measured intracellular Ca2+ signaling and mitochondrial thermogenesis and energy expenditure in r-irisin-treated H9C2 cells. The results showed that r-irisin, in a certain concentration rage, could activate PI3K-AKT and intracellular Ca2+ signaling and increase cellular oxygen consumption in H9C2 cells. Our study also suggests the existence of irisin-specific receptor on the membrane of H9C2 cells. In conclusion, irisin in a certain concentration rage increased myocardial cell metabolism, inhibited cell proliferation and promoted cell differentiation. These effects might be mediated through PI3K-AKT and Ca2+ signaling, which are known to activate expression of exercise-related genes such as follistatin and myocardin. This work supports the value of exercise, which promotes irisin release. 10.1371/journal.pone.0136816
    FNDC5/Irisin counteracts lipotoxic-induced apoptosis in hypoxic H9c2 cells. Moscoso Isabel,Cebro-Márquez María,Rodríguez-Mañero Moisés,González-Juanatey José Ramón,Lage Ricardo Journal of molecular endocrinology Irisin is a newly identified adipokine critical to modulate body metabolism, fatty acid metabolism and oxidative stress; recent evidence suggests a cardioprotective role in ischemic injury. Loss of cardiomyocytes during acute myocardial infarction is strongly associated with energetic changes and lipotoxic-induced apoptosis. Our aim was to study FNDC5/irisin's potential protective role against hypoxia and lipotoxicity, both related with myocardial infarction environment. H9c2 cells were treated with palmitate and/or irisin in normoxic/hypoxic conditions. Cell viability and apoptosis were assessed by MTT assay and annexin V/PI staining. Immunoblotting was used to confirm apoptotic cascade regulation. Irisin counteracts lipotoxic-induced apoptosis in hypoxic cardiomyoblasts by activating Akt signaling pathway suggesting the potential therapeutic role of irisin in ischemic heart disease. 10.1530/JME-19-0123
    Decreased saliva/serum irisin concentrations in the acute myocardial infarction promising for being a new candidate biomarker for diagnosis of this pathology. Aydin Suna,Aydin Suleyman,Kobat Mehmet Ali,Kalayci Mehmet,Eren Mehmet Nesimi,Yilmaz Musa,Kuloglu Tuncay,Gul Evrim,Secen Ozlem,Alatas Omer Dogan,Baydas Adil Peptides Irisin is a muscle-secreted protein. Cardiac muscle produces more irisin than skeletal muscle in response to acute exercise, and is associated with myocardial infarction (MI) in an experimental model induced by isoproterenol in rats. The timing and significance of its release in patients with acute myocardial infarction (AMI) needs further investigation. We have studied the relationship between serum/saliva irisin concentration and AMI in humans. Serum and saliva samples were taken within 3 days of admission in 11 patients with AMI and in 14 matched controls. Salivary gland irisin was detected immunohistochemically, and serum and saliva levels were measured by ELISA. The three major paired salivary glands (submandibular, sublingual and parotid) produce and release irisin into saliva. Troponin-I, CK, CK-MB concentrations in the AMI group gradually increased from up to 12h, while saliva and serum irisin gradually decreased from up to 48 h, compared with the control group (P<0.05). After 12h, troponin-I, CK, CK-MB started to decrease, while saliva and serum irisin started to increase at 72 h. Serum irisin levels correlated with age, while troponin I, CK-MB, and CK were correlated and with saliva irisin in AMI patients. Besides cardiac troponin and CK-MB, irisin adds new diagnostic information in AMI patients, and the gradual decrease of saliva/serum irisin over 48 h could be a useful biomarker. 10.1016/j.peptides.2014.04.002
    Irisin Ameliorates Hypoxia/Reoxygenation-Induced Injury through Modulation of Histone Deacetylase 4. Zhao Yu Tina,Wang Hao,Zhang Shouyan,Du Jianfeng,Zhuang Shougang,Zhao Ting C PloS one Irisin is a recently identified myokine which brings increases in energy expenditure and contributes to the beneficial effects of exercise through the browning of white adipose tissues. However, its effects in the heart remains unknown. This study sought to determine the effects of irisin on hypoxia/reoxygenation injury and its relationship with HDAC4. Wild type and stable HDAC4-overexpression cells were generated from H9c2 cardiomyoblasts. HDAC4 overexpression cells and wild type H9c2 cells were exposed to 24 hours of hypoxia followed by one hour of reoxygenation in vitro in the presence or absence of irisin (5 ng/ml). Cell cytotoxicity, apoptosis, mitochondrial respiration, and mitochondrial permeability transition pore (mPTP) were determined. Western blotting was employed to determine active-caspase 3, annexin V, and HDAC4 expression. As compared to wild type H9c2 group, HDAC4 overexpression remarkably led to a great increase in cell death as evident by the increased lactate dehydrogenase (LDH) leakage, ratio of caspase-3-positive cells as well as the upregulated levels of active-caspase 3 and annexin V shown by western blot analysis. In addition, HDAC4 overexpression also induced much severe mitochondrial dysfunction, as indicated by apoptotic mitochondria and increased mPTP. However, irisin treatment significantly attenuated all of these effects. Though irisin treatment did not influence the expression of HDAC4 at the transcriptional level, western blot analysis showed that HDAC4 protein levels decreased in a time-dependent way after administration of irisin, which is associated with the degradation of HDAC4 mediated by small ubiquitin-like modification (SUMO). Our results are the first to demonstrate that the protective effects of irisin in cardiomyoblasts exposed to hypoxia/reoxygenation might be associated with HDAC4 degradation. 10.1371/journal.pone.0166182
    Association of Serum Irisin Concentrations with Presence and Severity of Coronary Artery Disease. Deng Wen Medical science monitor : international medical journal of experimental and clinical research BACKGROUND Irisin, an exercise-induced myokine, is closely correlated with obesity and body mass index. Obesity is one risk factor of coronary artery disease (CAD). Therefore, the present study aimed to determine if serum irisin concentrations are correlated with the presence and severity of CAD. MATERIAL AND METHODS Serum irisin concentrations were determined in 350 patients with CAD and in 214 healthy subjects. The severity of CAD was assessed by coronary atherosclerosis index (CAI). RESULTS Serum irisin concentrations were significantly lower in CAD patients compared with healthy controls. Multivariable logistic regression analysis revealed that serum irisin concentrations were an independent determinant of the presence of CAD. In addition, Pearson correlation analysis showed that serum irisin concentrations were negatively correlated with CAI in CAD patients CONCLUSIONS Decreased serum irisin concentrations may be associated with the presence and severity of CAD. 10.12659/msm.897376
    Irisin vs. Treadmill Exercise in Post Myocardial Infarction Cardiac Rehabilitation in Rats. Archives of medical research BACKGROUND:Irisin is an exercise-induced myokine that could play a role in post-myocardial infarction (MI) cardiac rehabilitation. AIM OF THE STUDY:We investigated the ability of dihydromyricetin to mimic the effects of exercise on raising serum irisin and on enhancing cardiac function and remodeling following MI in rats. METHODS:MI was induced in albino rats by subcutaneous injection of isoproterenol (85 mg/kg) for 2 consecutive days at an interval of 24 h. One week post-MI, rats either underwent physical exercise by running on a motor-driven treadmill at 25 m/min, 30 min/d, 5 d/week or received orally dihydromyricetin 100 mg/kg/d, for 8 weeks. RESULTS:Exercise and dihydromyricetin raised serum irisin 1.8 and 1.9 folds as compared to sedentary rats (p <0.001) with no difference between both regimens (p = 0.992). There was an improvement of cardiac remodeling where β-myosin heavy chain level was not different in exercise and dihydromyricetin groups from normal group (p = 0.695, p = 0.470). The heart rate variability domains increased back to normal. However, exercise was superior to dihydromyricetin in improving cardiac contractility by increasing carotid blood flow, stroke volume and cardiac output to be insignificant from normal rats (p = 0.899, p = 0.850, p = 0.912). Meanwhile, treatment with dihydromyricetin showed reduction by 29% of carotid blood flow, 24% of stroke volume and 25% of cardiac output compared to normal rats (p <0.001). CONCLUSIONS:DHM could mimic the effect of exercise in stimulating irisin secretion but it is not as effective as exercise in improving myocardial contractility. 10.1016/j.arcmed.2019.05.009
    Circulating irisin levels are lower in patients with either stable coronary artery disease (CAD) or myocardial infarction (MI) versus healthy controls, whereas follistatin and activin A levels are higher and can discriminate MI from CAD with similar to CK-MB accuracy. Anastasilakis Athanasios D,Koulaxis Dimitrios,Kefala Nikoleta,Polyzos Stergios A,Upadhyay Jagriti,Pagkalidou Eirini,Economou Fotios,Anastasilakis Chrysostomos D,Mantzoros Christos S Metabolism: clinical and experimental BACKGROUND:Several myokines are produced by cardiac muscle. We investigated changes in myokine levels at the time of acute myocardial infarction (MI) and following reperfusion in relation to controls. METHODS:Patients with MI (MI Group, n=31) treated with percutaneous coronary intervention (PCI) were compared to patients with stable coronary artery disease (CAD) subjected to scheduled PCI (CAD Group, n=40) and controls with symptoms mimicking CAD without stenosis in angiography (Control Group, n=43). The number and degree of stenosis were recorded. Irisin, follistatin, follistatin-like 3, activin A and B, ALT, AST, CK and CK-MB were measured at baseline and 6 or 24h after the intervention. RESULTS:MI and CAD patients had lower irisin than controls (p<0.001). MI patients had higher follistatin, activin A, CK, CK-MB and AST than CAD patients and controls (all p≤0.001). None of the myokines changed following reperfusion. Circulating irisin was associated with the degree of stenosis in all patients (p=0.05). Irisin was not inferior to CK-MB in predicting MI while folistatin and activin A could discriminate MI from CAD patients with similar to CK-MB accuracy. None of these myokines was altered following PCI in contrast to CK-MB. CONCLUSIONS:Irisin levels are lower in MI and CAD implying that their production may depend on myocadial blood supply. Follistatin and activin A are higher in MI than in CAD suggesting increased release due to myocardial necrosis. They can predict MI with accuracy similar to CK-MB and their role in the diagnosis of MI remains to be confirmed by prospective large clinical studies. 10.1016/j.metabol.2017.05.002
    Irisin, a novel myokine is an independent predictor for sarcopenia and carotid atherosclerosis in dialysis patients. Lee Mi Jung,Lee Sul A,Nam Bo Young,Park Sungha,Lee Sang-Hak,Ryu Han Jak,Kwon Young Eun,Kim Yung Ly,Park Kyoung Sook,Oh Hyung Jung,Park Jung Tak,Han Seung Hyeok,Ryu Dong-Ryeol,Kang Shin-Wook,Yoo Tae-Hyun Atherosclerosis OBJECTIVE:In end-stage renal disease, deleterious effect of sarcopenia on cardiovascular disease has been explained mainly by chronic inflammation. However, evidence emerged that skeletal muscles mediate their protective effect against sarcopenia by secreting myokines. Therefore, we sought to investigate the effect of irisin, a recently introduced myokine, on the association between sarcopenia and cardiovascular disease in peritoneal dialysis (PD) patients. METHODS:Serum irisin concentrations were assessed by enzyme-linked immunosorbent assay in 102 prevalent PD patients and 35 age- and sex-matched controls. To determine sarcopenia and cardiovascular disease, anthropometric indices including mid-arm muscle circumference (MAMC) and carotid intima-media thickness (cIMT) were measured. RESULTS:Serum irisin concentrations were significantly lower in PD patients than in controls (184.2 ± 88.0 vs. 457.2 ± 105.5 ng/mL, P < 0.001). In PD patients, univariate linear regression analysis showed that serum irisin was positively correlated with MAMC and thigh circumference, but negatively correlated with residual renal function and cIMT. Multivariate analysis revealed that MAMC (per 1 cm increase, B = 8.78, 95% confidence interval [CI] = 0.77-16.79, P = 0.03) had an independent association with serum irisin. In addition, serum irisin was a significant independent predictor for carotid atherosclerosis even after adjustment for high-sensitivity C-reactive protein in PD patients (per 1 g/mL increase, odds ratio = 0.990, 95% CI = 0.982-0.997, P = 0.007). CONCLUSION:This study demonstrated that serum irisin was significantly associated with sarcopenia and carotid atherosclerosis in PD patients. Additional studies to provide a confirmation and examine possible mechanisms are warranted. 10.1016/j.atherosclerosis.2015.08.002
    Circulating irisin levels in heart failure with preserved or reduced ejection fraction: A pilot study. Silvestrini Andrea,Bruno Carmine,Vergani Edoardo,Venuti Angela,Favuzzi Angela Maria Rita,Guidi Francesco,Nicolotti Nicola,Meucci Elisabetta,Mordente Alvaro,Mancini Antonio PloS one Irisin, a recently discovered myokine, has been considered a prognostic factor in several cardiovascular diseases. Nevertheless, no data are available on the role of irisin in patients with heart failure (HF), both with preserved (HFpEF) or reduced (HFrEF) ejection fraction. We have therefore evaluated the circulating irisin levels in HFpEF and HFrEF patients, correlating them with metabolic parameters and total antioxidant capacity (TAC), as index of oxidative stress. Irisin was significantly higher in HFpEF than in HFrEF patients (7.72 ± 0.76 vs 2.77 ± 0.77 ng/ml, respectively). An inverse correlation between irisin and TAC was found in HFpEF, but not in HFrEF. Conversely, no correlation was present with HOMA index. These data support the hypothesis that a different pathophysiological mechanism is involved in the two HF subtypes, and oxidative stress modulates irisin secretion. 10.1371/journal.pone.0210320
    Irisin improves endothelial function in obese mice through the AMPK-eNOS pathway. Han Fang,Zhang Shuxian,Hou Ningning,Wang Di,Sun Xiaodong American journal of physiology. Heart and circulatory physiology Irisin is a novel hormone secreted by myocytes. Lower levels of irisin are independently associated with endothelial dysfunction in obese subjects. The objective of this study was to explore whether irisin exerts a direct vascular protective effect on endothelial function in high-fat-diet-induced obese mice. Male C57BL/6 mice were given chow or a high-fat diet with or without treatment with irisin. Aortic endothelial function was determined by measuring endothelium-dependent vasodilatation (EDV). Nitric oxide (NO) in the aorta was determined. The effect of irisin on the levels of AMP-activated protein kinase (AMPK), Akt, and endothelial NO synthase (eNOS) phosphorylation in endothelial cells was determined. Human umbilical vein endothelial cells were used to study the role of irisin in the AMPK-eNOS pathway. Acetylcholine-stimulated EDV was significantly lower in obese mice compared with control mice. Treatment of obese mice with irisin significantly enhanced EDV and improved endothelial function. This beneficial effect of irisin was partly attenuated in the presence of inhibitors of AMPK, Akt, and eNOS. Treatment of obese mice with irisin enhanced NO production and phosphorylation of AMPK, Akt, and eNOS in endothelial cells. These factors were also enhanced by irisin in human umbilical vein endothelial cells in vitro. Suppression of AMPK expression by small interfering RNA blocked irisin-induced eNOS and Akt phosphorylation and NO production. We have provided the first evidence that irisin improves endothelial function in aortas of high-fat-diet-induced obese mice. The mechanism for this protective effect is related to the activation of the AMPK-eNOS signaling pathway. 10.1152/ajpheart.00443.2015
    Lower irisin levels in coronary artery disease: a meta-analysis. Guo Wenwen,Zhang Baihui,Wang Xia Minerva endocrinologica INTRODUCTION:Irisin is a newly discovered myokine, which is involved in energy metabolism and associated with "browning" of the white adipose tissue, obesity, diabetes mellitus and metabolic syndrome. It is still uncertain that whether irisin level is associated with coronary artery disease. The purpose of this study was to explore the relationship between irisin levels and coronary artery disease. EVIDENCE ACQUISITION:A search of PubMed, MEDLINE, Elsevier Science Direct, Springer, Web of Science and China National Knowledge Infrastructure (CNKI) for studies published from 2000 to 2017 was undertaken to identify relevant studies. Case-control studies that reported the association between irisin levels and coronary artery disease were included. Methodological quality of the studies was assessed according to the Newcastle-Ottawa Scale. Random-efforts models were used to analyze the weighted mean difference (WMD) and its 95% confidence interval (CI). Subgroup analysis was performed to explore potential sources of heterogeneity. EVIDENCE SYNTHESIS:From 741 studies, 7 case-control studies involving 867 patients and 700 controls were selected for meta-analysis based on our inclusion and exclusion criteria. In these case-control studies, irisin concentrations were lower in coronary artery disease patients compared with healthy controls. In the meta-analysis, the pooled data indicated that irisin levels were -18.10 ng/mL ([95% CI: -35.53 to -0.68 ng/mL]; P<0.05) lower in patients with cardiovascular disease or atherosclerosis than healthy controls. CONCLUSIONS:This study confirmed that irisin levels were significantly lower in patients with coronary artery disease. 10.23736/S0391-1977.17.02663-3
    Relationship of Circulating Irisin with Body Composition, Physical Activity, and Cardiovascular and Metabolic Disorders in the Pediatric Population. Elizondo-Montemayor Leticia,Mendoza-Lara Gerardo,Gutierrez-DelBosque Gustavo,Peschard-Franco Mariana,Nieblas Bianca,Garcia-Rivas Gerardo International journal of molecular sciences Exercise-induced irisin, a recently discovered myokine, has been linked to insulin resistance, obesity, and other diseases in adults; however, information in children is scarce and contradictory. We analyzed the limited evidence of irisin's effects in children and adolescents, and its association with body composition, exercise training, cardiovascular risk factors, and metabolic diseases, as well as the results of dietetic interventions. Both positive and negative correlations between irisin concentrations and body mass index, fat mass, fat-free mass, and other anthropometric parameters were found. Likewise, contradictory evidence was shown associating irisin plasma levels with cardiovascular and metabolic parameters such as glucose, insulin resistance, and cholesterol and other lipid and fatty acid plasma levels in healthy children, as well as in those with obesity and the metabolic syndrome. Gender, puberty, and hormonal differences were also examined. Furthermore, important contradictory findings according to the type and duration of exercise and of dietetic interventions in healthy and unhealthy subjects were demonstrated. In addition, correlations between mother⁻infant relations and circulating irisin were also identified. This review discusses the potential role of irisin in health and disease in the pediatric population. 10.3390/ijms19123727
    Irisin regulates cardiac physiology in zebrafish. Sundarrajan Lakshminarasimhan,Yeung Chanel,Hahn Logan,Weber Lynn P,Unniappan Suraj PloS one Irisin is a myokine encoded in its precursor fibronectin type III domain containing 5 (FNDC5). It is abundantly expressed in cardiac and skeletal muscle, and is secreted upon the activation of peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1 alpha). We aimed to study the role of irisin on cardiac function and muscle protein regulation in zebrafish. Western blot analyses detected the presence of irisin protein (23 kDa) in zebrafish heart and skeletal muscle, and irisin immunoreactivity was detected in both tissues. Irisin siRNA treated samples did not show bands corresponding to irisin in zebrafish. In vitro studies found that treatment with irisin (0.1 nM) downregulated the expression of PGC-1 alpha, myostatin a, and b, while upregulating troponin C mRNA expression in zebrafish heart and skeletal muscle. Exogenous irisin (0.1 and 1 ng/g B.W) increased diastolic volume, heart rate and cardiac output, while knockdown of irisin (10 ng/g B.W) showed opposing effects on cardiovascular function. Irisin (1 and 10 ng/g B.W) downregulated PGC-1 alpha, myostatin a and b, and upregulated troponin C and troponin T2D mRNA expression. Meanwhile, knockdown of irisin showed opposing effects on troponin C, troponin T2D and myostatin a and b mRNAs in zebrafish heart and skeletal muscle. Collectively, these results identified muscle proteins as novel targets of irisin, and added irisin to the list of peptide modulators of cardiovascular physiology in zebrafish. 10.1371/journal.pone.0181461
    Adropin and Irisin in Patients with Cardiac Cachexia. Kalkan Ali Kemal,Cakmak Huseyin Altug,Erturk Mehmet,Kalkan Kübra Erol,Uzun Fatih,Tasbulak Omer,Diker Vesile Ornek,Aydin Suleyman,Celik Ahmet Arquivos brasileiros de cardiologia BACKGROUND:Cardiac cachexia is an important predictive factor of the reduction in survival of patients with heart failure with reduced ejection fraction. OBJECTIVES:The aims of the present study were to evaluate adropin and irisin levels in cachectic and non-cachectic subjects and the relationships between the levels of these proteins and clinical and laboratory parameters in patients with HFrEF. METHODS:The clinical records of patients who were admitted to the cardiology outpatient clinic for heart failure with reduced ejection fraction were screened. Cachectic patients were identified and assigned to the study group (n = 44, mean age, 65.4 ± 11.2 y; 61.4% men). Heart failure with reduced ejection fraction patients without weight loss were enrolled as the control group (n = 42, mean age, 61.0 ± 16.5 y; 64.3% men). The serum adropin and irisin levels of all patients were measured. A p-value < 0.05 was considered significant. RESULTS:Serum adropin and irisin levels were significantly higher in the cachexia group than in the controls (Adropin (ng/L); 286.1 (231.3-404.0) vs 213.7 (203.1-251.3); p < 0.001, Irisin (µg/mL); 2.6 (2.2-4.4) vs 2.1 (1.8-2.4); p = 0.001). Serum adropin and irisin levels were positively correlated with brain natriuretic peptide (BNP) levels and New York Heart Association (NYHA) class and negatively correlated with body mass index (BMI) and serum albumin levels (all p values: < 0.001). In a multivariate analysis, adropin was the only independent predictor of cachexia in the heart failure with reduced ejection fraction patients (OR: 1.021; 95% CI: 1.004-1.038; p = 0.017). CONCLUSIONS:The results suggest that adropin and irisin may be novel markers of cardiac cachexia in heart failure with reduced ejection fraction patients. Adropin and irisin are related with the severity of heart failure. 10.5935/abc.20180109
    Serum Irisin Level Can Predict the Severity of Coronary Artery Disease in Patients with Stable Angina. Efe Tolga Han,Açar Burak,Ertem Ahmet Göktuğ,Yayla Kadriye Gayretli,Algül Engin,Yayla Çağrı,Ünal Sefa,Bilgin Murat,Çimen Tolga,Kirbaş Özgür,Yeter Ekrem Korean circulation journal BACKGROUND AND OBJECTIVES:The recently discovered myokine irisin has a proposed role in adipose tissue metabolism. The aim of this study was to evaluate the relationship between serum irisin level and the coronary artery severity in patients with stable coronary artery disease (CAD). SUBJECTS AND METHODS:Sixty-three patients who underwent coronary angiography (CA) diagnosed with stable CAD and twenty-six patients with normal coronary artery (NCA) were enrolled in the study. Stable CAD patients were divided into two groups as high synergy between percutaneous coronary intervention with taxus and cardiac surgery (SYNTAX) score (≥23) and lower SYNTAX score (<23). Serum irisin level measurement was carried out using human irisin colorimetric enzyme-linked immunosorbent assay (ELISA) commercial kit (AG-45A-0046EK-KI01, Adipogen, San Diego, CA, USA) as recommended by the manufacturer's protocol. RESULTS:The patients with stable CAD with a higher SYNTAX score (score ≥23) had significantly lower serum irisin levels (127.91±55.38 ng/mL), as compared the patients with a low SYNTAX score (score <23) (224.69±92.99 ng/mL) and control group (299.54±123.20 ng/mL). Irisin levels showed significant differences between all groups (p<0.001). CONCLUSION:Serum irisin level is an independent predictor of coronary artery severity in patients with stable CAD. 10.4070/kcj.2016.0079
    Irisin Regulates Heme Oxygenase-1/Adiponectin Axis in Perivascular Adipose Tissue and Improves Endothelial Dysfunction in Diet-Induced Obese Mice. Hou Ningning,Du Gang,Han Fang,Zhang Jin,Jiao Xiaotong,Sun Xiaodong Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology AIMS:To determine whether irisin could improve endothelial dysfunction by regulating heme oxygenase-1(HO-1)/adiponectin axis in perivascular adipose tissue (PVAT) in obesity. METHODS:Male C57BL/6 mice were fed with a high-fat diet (HFD) with or without irisin treatment. Endothelium-dependent vasorelaxation of the thoracic aorta with or without PVAT (PVAT+ or PVAT-) was determined. Western blot was employed to determine the levels of HO-1 and adiponectin in PVAT. UCP-1, Cidea, and TNF-α gene expression in PVAT were tested by real-time PCR. RESULTS:The presence of PVAT significantly impaired endothelial function in the HFD mice. Treatment of HFD mice with irisin significantly restored this impairment and improved endothelial function in vivo or ex vivo. Incubated aortic rings (PVAT-) with PVAT-derived conditioned medium (CM) from HFD mice impaired endothelial function in control mice. This impairment was prevented by incubating the aortic rings (PVAT-) from HFD mice with PVAT-derived CM from irisin. However, the beneficial effects were partly attenuated in the presence of HO-1 inhibitor and adiponectin receptor blocking peptide. Treatment of HFD mice with irisin significantly increased NO production, protein levels of HO-1 and adiponectin, mRNA expressions of UCP-1 and Cidea, and decreased superoxide production and TNF-α expression in PVAT. CONCLUSION:Irisin improved endothelial function by modulating HO-1/ adiponectin axis in PVAT in HFD-induced obese mice. These findings suggest that regulating PVAT function may be a potential mechanism by which irisin improves endothelial function in obesity. 10.1159/000477864
    Type 2 diabetes with hypertensive patients results in changes to features of adipocytokines: Leptin, Irisin, LGR4, and Sfrp5. Li Baoxin,Yao Qi,Guo Shuqin,Ma Shuang,Dong Yuehua,Xin Huanhuan,Wang He,Liu Lifang,Chang Wenlong,Zhang Yunliang Clinical and experimental hypertension (New York, N.Y. : 1993) The incidence of hypertension and diabetes is increasing, it is reported that adipocytokines might be involved in the pathogenesis of diabetes and hypertension. We aimed to investigate the features of adipocytokines, included of Leptin, Irisin, LGR4, and Sfrp5 in type 2 diabetes mellitus (T2DM) patients with hypertension, simultaneously analyzed the connection of the alteration of adipocytokines with blood pressure and glucose. 424 patients with T2DM and 90 healthy subjects were included in the study. The patients with T2DM were divided into 4 groups based on the blood pressure. The levels of adipocytokines (Leptin, Irisin, LGR4, and Sfrp5) were determined by enzyme-linked immunosorbent assay (ELISA). Significantly higher levels of Leptin and lower levels of Irisin, LGR4 and Sfrp5 were seen in patients with diabetes compared with non-diabetes (P < 0.05), the mean values of Leptin level was ascending and Irisin, LGR4, and Sfrp5 levels were declining with promoting of blood pressure in hypertension as compared to the non-hypertension with diabetic patients. Multiple stepwise linear regression analysis showed that the concentrations of Leptin, Irisin, Sfrp5, and LGR4 were found to be closely associated with the control of blood pressure and glucose. Four adipocytokines might play different roles and closely relate to the occurrence and development of diabetes and hypertension. 10.1080/10641963.2018.1529779
    Irisin reverses platelet derived growth factor-BB-induced vascular smooth muscle cells phenotype modulation through STAT3 signaling pathway. Song Haibo,Xu Jia,Lv Nan,Zhang Yuzhu,Wu Fei,Li Huanjie,Shao Lei,Mu Qian,Wang Fang,Tang Dongqi,Fang Xu Biochemical and biophysical research communications Vascular smooth muscle cells (VSMCs) phenotype modulation toward a synthetic phenotype is the main cause of cardiovascular disease. As a newly discovered myokine, Irisin is thought to be a promising candidate for the treatment of metabolic disturbances, as well as cardiovascular disease. However, no evidence has been shown for the direct effect of Irisin on VSMCs phenotype modulation and its underling mechanisms. The aim of this study was to explore the effect of Irisin on VSMCs phenotype modulation and the mechanisms involved. In the present study, it was found that Irisin restored the PDGF-BB-induced VSMCs phenotype modulation which exhibited down-regulation of smooth muscle cells (SMC) expression and up-regulation of matrix synthesis related marker expression, as well as proliferative phenotype. Moreover, our research demonstrated that Irisin further activated STAT3 signaling pathways. Finally, by applying an STAT3 inhibitor, WP1066, we revealed the roles of STAT3 in the PDGF-BB-induced VSMCs phenotype modulation when they were treated with Irisin. Taken together, these results demonstrated that Irisin may play a crucial role in regulating VSMCs phenotype modulation via the STAT3 signaling pathway. 10.1016/j.bbrc.2016.07.052
    Irisin Lowers Blood Pressure by Improvement of Endothelial Dysfunction via AMPK-Akt-eNOS-NO Pathway in the Spontaneously Hypertensive Rat. Fu Jinjuan,Han Yu,Wang Jialiang,Liu Yukai,Zheng Shuo,Zhou Lin,Jose Pedro A,Zeng Chunyu Journal of the American Heart Association BACKGROUND:Exercise is a major nonpharmacological treatment for hypertension, but its underlying mechanisms are still not completely elucidated. Irisin, a polypeptide containing 112 amino acids, which is secreted mainly by skeletal muscle cells during exercise, exerts a protective role in metabolic diseases, such as diabetes mellitus and obesity. Because of the close relationship between irisin and metabolic diseases, we hypothesized that irisin may play a role in the regulation of blood pressure. METHODS AND RESULTS:Blood pressures of male Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) were monitored through the carotid artery. Our study found that acute intravenous injection of irisin reduced blood pressure in SHRs, but not WKY rats. Irisin, by itself, had no direct vasorelaxing effect in phenylephrine-preconstricted mesenteric arteries from SHRs. However, irisin augmented the acetylcholine-induced vasorelaxation in mesenteric arteries from SHRs that could be reversed by Nω-nitro-l-arginine-methyl ester (L-NAME; 100 μmol/L), indicating a role of nitric oxide (NO) in this action. Indeed, irisin increased NO production and phosphorylation of endothelial nirtic oxide synthase (eNOS) in endothelial cells. 5'-AMP-activated protein kinase (AMPK) was involved in the vasorelaxing effect of irisin because compound C (20 μmol/L), an AMPK inhibitor, blocked the irisin-mediated increase in phosphorylation of eNOS and protein kinase B (Akt) in endothelial cells and vasodilation in mesenteric arteries. CONCLUSIONS:We conclude that acute administration of irisin lowers blood pressure of SHRs by amelioration of endothelial dysfunction of the mesenteric artery through the AMPK-Akt-eNOS-NO signaling pathway. 10.1161/JAHA.116.003433
    The effect of iloprost and sildenafil, alone and in combination, on myocardial ischaemia and nitric oxide and irisin levels. Aydin Suna,Kuloglu Tuncay,Aydin Suleyman,Yardim Meltem,Azboy Davut,Temizturk Zeki,Kalkan Ali Kemal,Eren Mehmet Nesimi Cardiovascular journal of Africa AIM:Insufficient oxygen supply to organs and tissues due to reduced arterial or venous blood flow results in ischaemia, during which, although ATP production stops, AMP and adenosine continue to be produced from ATP. The fate of irisin, which causes the production of heat instead of ATP during ischaemia, is unknown. Iloprost and sildenafil are two pharmaceutical agents that mediate the resumption of reperfusion (blood supply) via vasodilatation during ischaemic conditions. Our study aimed to explore the effects of iloprost and sildenafil on irisin levels in the heart, liver and kidney tissues and whether these pharmaceutical agents had any impact on serum irisin and nitric oxide levels in rats with induced experimental myocardial ischaemia. METHODS:The study included adult male Sprague-Dawley rats aged 10 months and weighing between 250 and 280 g. The animals were randomly allocated to eight groups, with five rats in each group. The groups were: sham (control), iloprost (ILO), sildenafil (SIL), ILO + SIL, myocardial ischaemia (MI), MI + ILO, MI + SIL and MI + ILO + SIL. The treatment protocols were implemented before inducing ischaemia, which was done by occluding the left coronary artery with a plastic ligature for 30 minutes. Following the reperfusion procedure, all rats were sacrificed after 24 hours, and their heart, liver and kidney tissues and blood samples were collected for analyses. An immunohistochemical method was used to measure the change in irisin levels, the ELISA method to quantify blood irisin levels, and Griess' assay to determine nitric oxide (NO) levels in the serum and tissue. Myocardial ischaemia was confirmed based on the results of Masson's trichrome staining, as well as levels of troponin and creatine kinase MB. RESULTS:Irisin levels in biological tissue and serum dropped statistically significantly in the ischaemic group (MI), but were restored with ILO and SIL administration. Individual SIL administration was more potently restorative than individual ILO administration or the combined administration of the two agents. NO level, on the other hand, showed the opposite tendency, reaching the highest level in the MI group, and falling with the use of pharmaceutical agents. CONCLUSIONS:Individual or combined administration of ILO and SIL reduced myocardial ischaemia and NO levels, and increased irisin levels. Elevated levels of irisin obtained by drug administration could possibly contribute to accelerated wound recovery by local heat production. Sildenafil was more effective than iloprost in eliminating ischaemia and may be the first choice in offsetting the effects of ischaemia in the future. 10.5830/CVJA-2017-025
    Serum Irisin Predicts Mortality Risk in Acute Heart Failure Patients. Shen Shutong,Gao Rongrong,Bei Yihua,Li Jin,Zhang Haifeng,Zhou Yanli,Yao Wenming,Xu Dongjie,Zhou Fang,Jin Mengchao,Wei Siqi,Wang Kai,Xu Xuejuan,Li Yongqin,Xiao Junjie,Li Xinli Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology BACKGROUND/AIMS:Irisin is a peptide hormone cleaved from a plasma membrane protein fibronectin type III domain containing protein 5 (FNDC5). Emerging studies have indicated association between serum irisin and many major chronic diseases including cardiovascular diseases. However, the role of serum irisin as a predictor for mortality risk in acute heart failure (AHF) patients is not clear. METHODS:AHF patients were enrolled and serum was collected at the admission and all patients were followed up for 1 year. Enzyme-linked immunosorbent assay was used to measure serum irisin levels. To explore predictors for AHF mortality, the univariate and multivariate logistic regression analysis, and receiver-operator characteristic (ROC) curve analysis were used. To determine the role of serum irisin levels in predicting survival, Kaplan-Meier survival analysis was used. RESULTS:In this study, 161 AHF patients were enrolled and serum irisin level was found to be significantly higher in patients deceased in 1-year follow-up. The univariate logistic regression analysis identified 18 variables associated with all-cause mortality in AHF patients, while the multivariate logistic regression analysis identified 2 variables namely blood urea nitrogen and serum irisin. ROC curve analysis indicated that blood urea nitrogen and the most commonly used biomarker, NT-pro-BNP, displayed poor prognostic value for AHF (AUCs ≤ 0.700) compared to serum irisin (AUC = 0.753). Kaplan-Meier survival analysis demonstrated that AHF patients with higher serum irisin had significantly higher mortality (P<0.001). CONCLUSION:Collectively, our study identified serum irisin as a predictive biomarker for 1-year all-cause mortality in AHF patients though large multicenter studies are highly needed. 10.1159/000477867
    Irisin Protects Heart Against Ischemia-Reperfusion Injury Through a SOD2-Dependent Mitochondria Mechanism. Wang Zhen,Chen Ken,Han Yu,Zhu Hua,Zhou Xinyu,Tan Tao,Zeng Jing,Zhang Jun,Liu Yukai,Li Yu,Yao Yonggang,Yi Jianxun,He Duofen,Zhou Jingsong,Ma Jianjie,Zeng Chunyu Journal of cardiovascular pharmacology Irisin, a muscle-origin protein derived from the extracellular domain of the fibronectin domain-containing 5 protein (FNDC5), has been shown to modulate mitochondria welfare through paracrine action. Here, we test the hypothesis that irisin contributes to cardioprotection after myocardial infarction by preserving mitochondrial function in cardiomyocytes. Animal model studies show that intravenous administration of exogenous irisin produces dose-dependent protection against ischemia/reperfusion (I/R)-induced injury to the heart as reflected by the improvement of left ventricular ejection fraction and the reduction in serum level of cTnI (n = 15, P < 0.05). I/R-induced apoptosis of cardiomyocytes is reduced after irisin treatment. The irisin-mediated protection has, at least in part, an effect on mitochondrial function because administration of irisin increases irisin staining in the mitochondria of the infarct area. Irisin also reduces I/R-induced oxidative stress as determined by mitochondrial membrane potential evaluation and superoxide FLASH event recording (n = 4, P < 0.05). The interaction between irisin and superoxide dismutase2 (SOD2) plays a key role in the protective process because irisin treatment increases SOD activity (n = 10, P < 0.05) and restores the mitochondria localization of SOD2 in cardiomyocytes (n = 5, P < 0.05). These results demonstrate that irisin plays a protective role against I/R injury to the heart. Targeting the action of irisin in mitochondria presents a novel therapeutic intervention for myocardial infarction. 10.1097/FJC.0000000000000608
    Association of serum concentrations of irisin and the adipokines adiponectin and leptin with epicardial fat in cardiovascular surgery patients. Kaneda Hiroyuki,Nakajima Toshiaki,Haruyama Akiko,Shibasaki Ikuko,Hasegawa Takaaki,Sawaguchi Tatsuya,Kuwata Toshiyuki,Obi Syoutarou,Arikawa Takuo,Sakuma Masashi,Amano Hirohisa,Toyoda Shigeru,Fukuda Hirotsugu,Inoue Teruo PloS one Epicardial fat located adjacent to the heart and coronary arteries is associated with increased cardiovascular risk. Irisin is a myokine produced by skeletal muscle after physical exercise, and originally described as a molecule able to promote the browning of white adipose tissue and energy expenditure. In order to decrease cardiovascular risk, it has been proposed as a promising therapeutic target in obesity and type 2 diabetes. We investigated the relationships between serum concentrations of irisin and the adipokines adiponectin and leptin and body fat including epicardial fat in patients undergoing cardiovascular surgery. We obtained serum samples from 93 patients undergoing cardiovascular surgery (age 69.6 (SD 12.8) years, BMI 24.1 ± 4.8 kg/m2). Computed tomography (CT) and echocardiographic data were obtained from the routine preoperative examination. Subcutaneous fat area (SFA, cm2) and visceral fat area (VFA, cm2) near the umbilicus were automatically measured using the standard fat attenuation range. Epicardial fat area (EFA, cm2) was measured at the position where the heart became a long axis image with respect to the apex of the heart in the coronal section image. Total body fat mass, body fat percentage, and skeletal muscle volume (SMV) were estimated using bioelectrical impedance analysis (BIA). Serum irisin concentration was measured by enzyme-linked immunosorbent assay, and compared with adiponectin and leptin concentrations. The data were also compared with the clinical biochemical data. EFA was strongly correlated with BMI (P = 0.0001), non-HDL-C (P = 0.029), TG (P = 0.004), body fat mass (P = 0.0001), and body fat percentage (P = 0.0001). Serum leptin concentration showed a significant positive correlation with BMI (P = 0.0001) and TG (P = 0.001). Adiponectin, but not irisin, showed a significant negative correlation with BMI (P = 0.006) and TG (P = 0.001). Serum leptin level had a significant positive correlation with EFA, VFA, and SFA. In contrast, the serum adiponectin level was significantly negatively correlated with EFA, VFA, and SFA. The serum irisin level was also negatively correlated with EFA (r = -0.249, P = 0.015), and SFA (r = -0.223, P = 0.039), and tended to correlate with VFA (r = -0.198, P = 0.067). The serum level of adiponectin was negatively correlated with that of leptin (r = -0.296, P = 0.012), but there were no significant correlations between irisin and either adiponectin or leptin. Multivariate linear regression demonstrated that EFA showed a positive association with serum leptin level (β = 0.438, P = 0.0001) and a negative correlation with serum irisin level (β = -0.204, P = 0.038) and serum adiponectin level (β = -0.260, P = 0.015) after adjusting for age, sex, and BMI. The present study provided the first evidence of associations of the serum irisin and adipokines (adiponectin and leptin) concentrations with epicardial fat in cardiovascular surgery patients. Irisin may play a role in preventing excess adiposity including epicardial fat, and consequently cardiovascular risk in patients. 10.1371/journal.pone.0201499
    Lower Serum Irisin Levels Are Associated with Increased Vascular Calcification in Hemodialysis Patients. He Lian,He Wan-Yu,A La-Ta,Yang Wen-Ling,Zhang Ai-Hua Kidney & blood pressure research BACKGROUND/AIMS:Vascular calcification, which involves an active cellular transformation of vascular smooth muscle cells into bone forming cells, is prevalent and predicts mortality in dialysis patients. Its mechanisms are complex and unclear. We presume that irisin, a newly identified myokine also may play roles in vascular calcification in hemodialysis patients. This study aims to evaluate serum irisin levels and establish their relation to vascular calcification and other parameters in hemodialysis patients. METHODS:A total of 150 patients on maintenance hemodialysis treatment and 38 age- and sex-matched healthy controls were enrolled in this cross-sectional study. Serum irisin concentrations were measured by ELISA. Vascular calcification was evaluated by abdominal aortic calcification scores. RESULTS:Serum irisin concentrations were significantly lower in hemodialysis patients than in controls [52.8 (22.0, 100.0) vs. 460.8 (434.8, 483.4) ng/ml, P<0.01]. In addition, irisin was negatively correlated with the parathyroid hormone level (P=0.01). The HD patients with vascular calcification showed significantly lower serum irisin concentrations [39.0 (21.7, 86.2) vs.79.0 (39.5, 130.2) ng/mL, P<0.01]. Compared with the group without vascular calcification multivariate logistic regression analyses revealed that serum irisin, HD vintage and age were significant independent determinant factors for vascular calcification in HD patients. CONCLUSION:Our results are the first to provide a clinical evidence of the association between serum irisin and vascular calcification in HD patients. Lower irisin levels, long-term hemodialysis and old ages are independent risk factors in HD patients. 10.1159/000487689
    The diagnostic value of the serum irisin level in patients with acute pericarditis and acute myopericarditis. Gunaydin M,Ozer V,Kalkan A,Ozer S,Sahin A,Sahin M,Karahan S C,Dogramaci S,Tatli O,Gunduz A Bratislavske lekarske listy OBJECTIVE:This preliminary study aims to examine a change in the blood levels of irisin in patients with acute pericarditis (AP) and acute myopericarditis (AMP) and examine the diagnostic value of the serum irisin level in AP and AMP. METHODS:10 patients, who applied to the emergency service and cardiology clinic with chest pain and who were diagnosed with AP and 5 patients, who were diagnosed with AMP as a result of routine examinations, were included in the study. The basal laboratory parameters, echocardiography findings and serum irisin levels of the patients and during check one month later were examined. RESULTS:While the basal irisin levels were found to be significantly low in the AMP group and high during the check (6.6 ± 1.58, 8.19 ± 1.43, respectively), no statistically significant difference was determined (p = 0.23). It was observed that the basal and control irisin levels did not vary significantly in the AP group (8.03 ± 1.6, 8.19 ± 1.43, respectively) (p = 0.84). CONCLUSION:In this preliminary study, the basal irisin levels were found to be significantly low in the AMP group, while there was no statistically significant difference between the basal irisin levels and control irisin levels in the AP and AMP groups (Tab. 5, Ref. 17). 10.4149/BLL_2018_117
    Irisin plays a pivotal role to protect the heart against ischemia and reperfusion injury. Wang Hao,Zhao Yu Tina,Zhang Shouyan,Dubielecka Patrycja M,Du Jianfeng,Yano Naohiro,Chin Y Eugene,Zhuang Shougang,Qin Gangjian,Zhao Ting C Journal of cellular physiology Irisin, a newly identified hormone, is critical to modulating body metabolism, thermogenesis and reducing oxidative stresses. However, whether irisin protects the heart against myocardial ischemia and reperfusion (I/R) injury remains unknown. In this study, we determine the effect of irisin on myocardial I/R injury in the Langendorff perfused heart and cultured myocytes. Adult C57/BL6 mice were treated with irisin (100 mg/kg) or vehicle for 30 min to elicit preconditioning. The isolated hearts were subjected to 30 min ischemia followed by 30 min reperfusion. Left ventricular function was measured and infarction size were determined using by tetrazolium staining. Western blot was employed to determine myocardial SOD-1, active-caspase 3, annexin V, p38, and phospho-p38. H9c2 cardiomyoblasts were exposed to hypoxia and reoxygenation for assessment of the effects of irisin on mitochondrial respiration and mitochondrial permeability transition pore (mPTP). Irisin treatment produced remarkable improvements in ventricular functional recovery, as evident by the increase in RPP and attenuation in LVEDP. As compared to the vehicle treatment, irisin resulted in a marked reduction of myocardial infarct size. Notably, irisin treatment increased SOD-1 and p38 phosphorylation, but suppressed levels of active-caspase 3, cleaved PARP, and annexin V. In cardiomyoblasts exposed to hypoxia/reoxygenation, irisin treatment significantly attenuated hypoxia/reoxygenation (H/R), as indicated by the reduction of lactate dehydrogenase (LDH) leakage and apoptotic cardiomyocytes. Furthermore, irisin treatments suppressed the opening of mPTP, mitochondrial swelling, and protected mitochondria function. Our results indicate that irisin serves as a novel approach to eliciting cardioprotection, which is associated with the improvement of mitochondrial function. 10.1002/jcp.25857
    TRPV4 is involved in irisin-induced endothelium-dependent vasodilation. Ye Li,Xu Mengnan,Hu Min,Zhang Hai,Tan Xianming,Li Qing,Shen Bing,Huang Junhao Biochemical and biophysical research communications Irisin, an exercise-induced myokine, induces conversion of white into brown adipocytes, promoting mitochondrial biogenesis and energy expenditure. Irisin has a vascular protective effect on endothelial function in animals, including humans. Defects in irisin signaling pathways result in endothelial dysfunction in obesity and diabetes. However, the mechanisms underlying the effects of irisin on endothelial function have not been elucidated. Transient receptor potential vanilloid subtype 4 (TRPV4) channels are one of the most important Ca-permeable cation channels in vascular endothelial cells. In this study, we hypothesized that irisin may induce endothelium-dependent vasodilation by activating Ca influx into endothelial cells via TRPV4 channels. In primary cultured rat mesenteric artery endothelial cells, irisin caused an increase in [Ca] due to extracellular Ca influx rather than release from Ca stores. Moreover, irisin-induced increases in [Ca] were completely abolished by a TRPV4 inhibitor. In addition, irisin induced endothelium-dependent vasodilation of rat mesenteric arteries. However, irisin had no effect on endothelium-independent vasodilation. Furthermore, irisin-induced vasodilation was fully abolished in the presence of a TRPV4 inhibitor, indicating the involvement of TRPV4 channels in endothelium-dependent vasodilation. This study provides the first evidence that irisin-induced endothelium-dependent vasodilation is related to the stimulation of extracellular Ca influx via TRPV4 channels in rat mesenteric arteries. 10.1016/j.bbrc.2017.10.160
    Serum irisin levels are associated with adverse cardiovascular outcomes in patients with acute myocardial infarction. Hsieh I-Chang,Ho Ming-Yun,Wen Ming-Shien,Chen Chun-Chi,Hsieh Ming-Jer,Lin Chia-Pin,Yeh Jih-Kai,Tsai Ming-Lung,Yang Chia-Hung,Wu Victor Chien-Chia,Hung Kuo-Chun,Wang Chun-Chieh,Wang Chao-Yung International journal of cardiology Irisin, a recently identified myokine, regulates mitochondrial function and energy expenditure. The concentration of irisin is significantly altered after ST-elevation myocardial infarction (STEMI). We hypothesized that serum irisin concentration is associated with adverse cardiovascular outcomes after myocardial infarction. Serum irisin concentrations were measured using enzyme-linked immunosorbent assay (ELISA) in 399 patients 28d after the onset of STEMI in a prospective single-center cohort study. We assessed the association between irisin concentrations and adverse cardiovascular events during a 3-year follow-up. The excess risks of cardiovascular mortality, stroke, heart failure, and revascularization were predominantly seen among those with the highest concentrations of irisin, with concentrations higher than 75th percentile of the overall distribution had a ~4-fold increase in risk (hazard ratio=3.96, 95% confidence interval 1.55 to 10.11, P<0.01). Our findings showed that serum concentrations of irisin are elevated in post-STEMI patients with increased risk for adverse cardiovascular events. Novel therapies targeting irisin may represent a new direction in the treatment of STEMI. 10.1016/j.ijcard.2017.11.072
    Irisin ameliorates angiotensin II-induced cardiomyocyte apoptosis through autophagy. Li Ruli,Wang Xiaoxiao,Wu Sisi,Wu Yao,Chen Hongying,Xin Juanjuan,Li He,Lan Jie,Xue Kunyue,Li Xue,Zhuo Caili,He Jinhan,Tang Chao-Shu,Jiang Wei Journal of cellular physiology Cardiac hypertrophy is the main cause of heart failure and sudden death in patients. But the pathogenesis is unclear. Angiotensin II may contribute to cardiac hypertrophy in response to pressure overload. In angiotensin II-treated cardiomyocytes, there is a larger cross-sectional area, more apoptosis cells, and a reduction of irisin expression. An increase in P62, an autophagy flux index, as well as LC3II, were observed in cardiomyocytes after angiotensin II-induced injury. Surprisely, irisin supplementation increased LC3II expression and decreased P62 expression, consisted of results of RFP-GFP-LC3B adenovirus transfection, and reduced cardiomyocyte apoptosis, meanwhile, the protection of irisin was reversed by the autophagy inhibitor 3-methyladenine. In animal experiments, overexpression of irisin reduced cardiomyocyte apoptosis and alleviated myocardial hypertrophy caused by pressure overload. The above results indicate that irisin-induced protective autophagy and alleviated the apoptosis signaling pathway in cardiomyocytes, consequently reducing cardiomyocyte apoptosis after angiotensin II-induced injury. Hence, increasing irisin expression may be a new way to improve cardiac function and quality of life in patients with cardiac hypertrophy. 10.1002/jcp.28382
    Exercise-induced myokine FNDC5/irisin functions in cardiovascular protection and intracerebral retrieval of synaptic plasticity. Zhou Xin,Xu MengMeng,Bryant Joseph L,Ma Jianjie,Xu Xuehong Cell & bioscience Physical exercise is well known to benefit human health at every age. However, the exact mechanism through which physical exercise improves health remains unknown. Recent studies into exercise-induced myokine FNDC5/irisin, a newly discovered hormone, have begun to shed light on this mystery. Exercise-induced myokine FNDC5/irisin have been shown to be protective against cardiovascular damage post ischemic event, improve function in the neurons of Alzheimer's disease patients, and have been implicated in macrophage and adipocyte regulation. Elegantly designed experiments have shown FNDC5/irisin to promote Nkx2.5 cardiac progenitor cell dependent cardiac regeneration, neovascularization, and reduce cardiac fibrosis. It has also been shown to improve macrophage function, which may protect against injuries to the cardiac conduction system. Similarly, FNDC5/irisin knockout mice have been shown to have reduced memory performance, while peripheral overexpression of FNDC5/irisin has been shown to improve memory impairment in a murine Alzheimer's disease model. Finally, FNDC5/irisin has been linked to regulation of osteocytes and adipocytes by signaling through the cytoplasmic membrane integrated protein aV/b5 integrin, the first known receptor for this newly discovered hormone. Although these recent discoveries have cemented the importance of FNDC5/irisin, many details regarding how FNDC5/irisin fits into the physiology of exercise benefits remain unknown and are deserving of future inquiry. 10.1186/s13578-019-0294-y
    Excessive irisin increases oxidative stress and apoptosis in murine heart. Ho Ming-Yun,Wen Ming-Shien,Yeh Jih-Kai,Hsieh I-Chang,Chen Chun-Chi,Hsieh Ming-Jer,Tsai Ming-Lung,Yang Chia-Hung,Wu Victor Chien-Chia,Hung Kuo-Chun,Wang Chun-Chieh,Wang Chao-Yung Biochemical and biophysical research communications Irisin is an exercise-related myokine. The abundance of irisin is associated with many diseases, such as myocardial infarction, chronic kidney disease, metabolic syndrome, obesity, and diabetes mellitus. In cardiomyocytes, irisin modulates the mitochondrial thermogenesis, regulates ischemic responses, and affects calcium signaling. Previous studies suggested that irisin increases cardiomyoblast mitochondrial functions and protects ischemic and reperfusion injury in ex vivo murine heart. In human, clinical studies have shown that acute myocardial infarction patients with more elevated serum irisin abundances are associated with increased major adverse cardiovascular events. However, the mechanisms responsible for this discrepancy between in myocardial infarction patients and ex vivo murine heart is unclear. Based on the clinical observations, we hypothesized that excessive irisin might lead to mitochondrial dysfunctions and cardiomyocyte damages. Our data showed that overexpression of irisin in mice with the adenovirus resulted in enhanced mitochondrial respiration with a higher oxygen consumption rate. Enhanced irisin expression in heart and irisin treatment in cardiomyocytes increased reactive oxygen species production. Furthermore, irisin treatment in cardiomyocytes enhanced the apoptosis and the cleaved caspase 9 levels in hypoxic condition. Pathway analysis in the murine heart with the overexpression of irisin showed that angiopoietin-Tie2, IL-8, IL-13, TGF-β, and thrombopoietin signaling were affected by irisin. Collectively, these results supported that excessive irisin causes mitochondrial overdrive with a higher reactive oxygen species production, which results in increased apoptosis of cardiomyocytes in a hypoxic environment. 10.1016/j.bbrc.2018.07.005
    Correlation between the blood level of irisin and the severity of acute myocardial infarction in exercise-trained rats. Bashar Shaimaa M,Samir El-Sherbeiny Shereen M,Boraie Mohamed Z Journal of basic and clinical physiology and pharmacology Background Acute myocardial infarction is a major cause of death all over the world. Irisin is a novel myokine released after exercise. This work aimed to study the correlation between the serum irisin level and the severity of the acute myocardial infarction in the exercise-trained rats. Methods Forty-eight male rats were classified into four groups (12 for each): group I, control sedentary (C); group II, exercise-trained (EX) (swimming for 8 weeks); group III, isoprenaline-induced infarct (MI); and group IV, exercise-trained infarct (EX-MI) (swimming for 8 weeks followed by isoprenaline-induced infarction). ECG was recorded at start and end of the study, before and after induction of infarction. The serum level of irisin, lipid peroxidation [malondialdehyde (MDA)], total antioxidant status (TAS), creatine phosphokinase-MB (CK-MB), and troponin I was determined. The hearts were excised for histopathology and immunohistochemistry for caspase-3. Results The infarct rats showed significant prolongation in QTc interval and elevation in the ST segment as well as significant elevation of serum CK-MB, troponin I, and MDA, whereas TAS and serum irisin level were significantly decreased. With exercise, we observed a high positive correlation between the serum irisin and QRS duration (+0.643), amplitude (+0.860), and TAS (+0.887). In addition, there was a high negative correlation between the serum irisin and ST elevation (-0.865), QTc (-0.886), CK-MB (-0.891), troponin (-0.882), and MDA (-0.868). This was confirmed by the negative correlation between serum irisin and both collagen deposition and caspase-3 expression (-0.823 and -0.822, respectively). Conclusions We recommend regular exercise or taking recombinant irisin as a supplement to protect at-risk individuals against acute myocardial infarction. 10.1515/jbcpp-2018-0090
    Irisin alleviates pressure overload-induced cardiac hypertrophy by inducing protective autophagy via mTOR-independent activation of the AMPK-ULK1 pathway. Li Ru-Li,Wu Si-Si,Wu Yao,Wang Xiao-Xiao,Chen Hong-Ying,Xin Juan-Juan,Li He,Lan Jie,Xue Kun-Yue,Li Xue,Zhuo Cai-Li,Cai Yu-Yan,He Jin-Han,Zhang Heng-Yu,Tang Chao-Shu,Wang Wang,Jiang Wei Journal of molecular and cellular cardiology In hypertrophic hearts, autophagic flux insufficiency is recognized as a key pathology leading to maladaptive cardiac remodeling and heart failure. This study aimed to illuminate the cardioprotective role and mechanisms of a new myokine and adipokine, irisin, in cardiac hypertrophy and remodeling. Adult male wild-type, mouse-FNDC5 (irisin-precursor)-knockout and FNDC5 transgenic mice received 4 weeks of transverse aortic constriction (TAC) alone or combined with intraperitoneal injection of chloroquine diphosphate (CQ). Endogenous FNDC5 ablation aggravated and exogenous FNDC5 overexpression attenuated the TAC-induced hypertrophic damage in the heart, which was comparable to the protection of irisin against cardiomyocyte hypertrophy induced by angiotensin II (Ang II) or phenylephrine (PE). Accumulated autophagosome and impaired autophagy flux occurred in the TAC-treated myocardium and Ang II- or PE-insulted cardiomyocytes. Irisin deficiency caused reduced autophagy and aggravated autophagy flux failure, whereas irisin overexpression or supplementation induced protective autophagy and improved autophagy flux, which were reversed by autophagy inhibitors Atg5 siRNA, 3-MA and CQ. Irisin boosted the activity of only AMPK but not Akt and MAPK family members in hypertrophic hearts and cultured cardiomyocytes and further activated ULK1 at Ser555 but not Ser757 and did not affect the mTOR-S6K axis. Blockage of AMPK and ULK1 with compund C and SBI-0206965, respectively, both abrogated irisin's protection against cardiomyocyte hypertrophic injury and reversed its induction of both autophagy and autophagy flux. Our results suggest that irisin protects against pressure overload-induced cardiac hypertrophy by inducing protective autophagy and autophagy flux via activating AMPK-ULK1 signaling. 10.1016/j.yjmcc.2018.07.250
    The association between serum irisin levels and cardiovascular disease in diabetic patients. Khorasani Zahra Mazloum,Bagheri Ramin Khameneh,Yaghoubi Mohammad Ali,Chobkar Saeed,Aghaee Monavvar Afzal,Abbaszadegan Mohammad Reza,Sahebkar Amirhossein Diabetes & metabolic syndrome BACKGROUND:Cardiovascular disease is the most common cause of mortality and morbidity in diabetic patients. Insulin resistance has been shown to be reduced by the secretion of irisin from muscle and adipose tissues. This study was aimed at determining the relationship between serum irisin levels and angiographically defined coronary artery disease (CAD) in type II diabetic patients. METHODS:In this case-control study, 30 diabetic subjects with angiographically defined CAD were compared with 30 age- and sex-matched diabetic subjects without CAD in terms of clinical and laboratory parameters including serum irisin levels. RESULTS:Serum levels of Irisin were significantly higher in the diabetic group without CAD compared with the group with CAD (P = 0.048). Serum irisin levels showed a significant positive correlation with BMI (r = 0.374, P = 0.004) and fasting insulin (r = 0.303, P = 0.021), and a significant negative correlation with diabetes duration (r = -0.384, P = 0.002). Based on the results of the binary logistic regression model, circulating levels of irisin were associated with the presence of CAD in diabetes (p = 0.038) after adjusting for potential confounders. CONCLUSION:Serum irisin levels were lower in the diabetic patients with cardiovascular complication compared with the uncomplicated diabetic patients. Therefore, additional larger scale studies are needed to determine the role of irisin in monitoring CAD in diabetic patients. 10.1016/j.dsx.2018.11.050
    Novel adipokines vaspin and irisin as risk biomarkers for cardiovascular diseases in type 2 diabetes mellitus. El-Lebedy Dalia H,Ibrahim Alshaymaa A,Ashmawy Ingy O Diabetes & metabolic syndrome AIMS:Vaspin and irisin are novel cytokines proposed as potential new biomarkers of insulin resistance and endothelial dysfunction. This work is to investigate circulating levels of vaspin and irisin in patients with type 2 diabetes mellitus (T2DM) with and without cardiovascular disease (CVD) to study potential association with disease risk. MATERIALS AND METHODS:Circulating levels of vaspin and irisin were assayed in serum from 135 T2DM patients (with and without CVD) and 70 control subjects by ELISA. RESULTS:Vaspin levels were significantly higher in T2DM patients than in control subjects (6798 ± 3540 pg/ml vs. 3215 ± 3209 pg/ml, p = 0.001) and in CVD patients than in non-CVD patients (7417.3 ± 3507.6 pg/ml vs. 6017.3 ± 3606.4 pg/ml, p = 0.001), with significant positive correlations with BMI, FPG, serum insulin and HOMA-IR. Irisin levels were significantly lower in T2DM patients than in controls (71.15 ± 67.57 ng/ml vs.127 ± 71.57 ng/ml, p = 0.004), and in CVD patients than in non-CVD patients (55.77 ± 54.82 ng/ml vs. 115.5 ± 67 ng/ml, p = 0.003), with significant correlations with HbA1c, HOMA-IR and BMI in diabetic patients, and with HbA1c and TG in CVD patients. Elevated levels of vaspin was associated with 1.7 times increased CVD risk (p = 0.001, OR = 1.7, 95%CI = 1.21-2.39), while lower levels of irisin associated with 1.6 times increased CVD risk (p = 0.007, OR = 1.6, 95%CI = 1.45-2.28). ROC analysis indicated serum vaspin and irisin as independent CVD risk biomarkers with sensitivity, 94% and 73.7%, and specificity, 74% and 74.1%; respectively. CONCLUSION:Our results indicate that circulating vaspin and irisin are potential new independent CVD risk biomarkers in T2DM. 10.1016/j.dsx.2018.04.025
    Irisin promotes cardiac progenitor cell-induced myocardial repair and functional improvement in infarcted heart. Zhao Yu Tina,Wang Jianguo,Yano Naohiro,Zhang Ling X,Wang Hao,Zhang Shouyan,Qin Gangjian,Dubielecka Patrycja M,Zhuang Shougang,Liu Paul Y,Chin Y Eugene,Zhao Ting C Journal of cellular physiology Irisin, a newly identified hormone and cardiokine, is critical for modulating body metabolism. New evidence indicates that irisin protects the heart against myocardial ischemic injury. However, whether irisin enhances cardiac progenitor cell (CPC)-induced cardiac repair remains unknown. This study examines the effect of irisin on CPC-induced cardiac repair when these cells are introduced into the infarcted myocardium. Nkx2.5 CPC stable cells were isolated from mouse embryonic stem cells. Nkx2.5 CPCs (0.5 × 10 ) were reintroduced into the infarcted myocardium using PEGlylated fibrin delivery. The mouse myocardial infarction model was created by permanent ligation of the left anterior descending (LAD) artery. Nkx2.5 CPCs were pretreated with irisin at a concentration of 5 ng/ml in vitro for 24 hr before transplantation. Myocardial functions were evaluated by echocardiographic measurement. Eight weeks after engraftment, Nkx2.5 CPCs improved ventricular function as evident by an increase in ejection fraction and fractional shortening. These findings are concomitant with the suppression of cardiac hypertrophy and attenuation of myocardial interstitial fibrosis. Transplantation of Nkx2.5 CPCs promoted cardiac regeneration and neovascularization, which were increased with the pretreatment of Nkx2.5 CPCs with irisin. Furthermore, irisin treatment promoted myocyte proliferation as indicated by proliferative markers Ki67 and phosphorylated histone 3 and decreased apoptosis. Additionally, irisin resulted in a marked reduction of histone deacetylase 4 and increased p38 acetylation in cultured CPCs. These results indicate that irisin promoted Nkx2.5 CPC-induced cardiac regeneration and functional improvement and that irisin serves as a novel therapeutic approach for stem cells in cardiac repair. 10.1002/jcp.27037
    Adropin and irisin: New biomarkers of cardiac status in patients with end-stage renal disease? A preliminary study. Kałużna Małgorzata,Pawlaczyk Krzysztof,Schwermer Krzysztof,Hoppe Krzysztof,Człapka-Matyasik Magdalena,Ibrahim Aisha Yusuf,Sawicka-Gutaj Nadia,Minczykowski Andrzej,Ziemnicka Katarzyna,Oko Andrzej,Ruchała Marek Advances in clinical and experimental medicine : official organ Wroclaw Medical University BACKGROUND:The new polypeptide hormones adropin and irisin have a broad impact on human metabolism and energy homeostasis. They could be potential biomarkers of cardiac injury. In end-stage renal disease (ESRD), the clinical importance of adropin and irisin is yet to be investigated. OBJECTIVES:The aim of this study was to determine the relationship between these peptides and cardiac status in ESRD patients. MATERIAL AND METHODS:Seventy-nine ESRD patients on hemodialysis (HD), peritoneal dialysis (PD) or after renal transplantation (Tx), and 40 healthy, ageand sex-matched controls (CON) were included in this study. Serum concentrations of adropin and irisin were measured with enzyme-linked immunosorbent assay (ELISA). Cardiac status was estimated by transthoracic echocardiography and the plasma concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT). RESULTS:The levels of irisin were significantly lower in HD patients as compared to CON. During HD sessions, the concentrations of adropin did not change significantly, whereas the concentrations of irisin increased with borderline significance. Positive correlations were evident between adropin concentration and cTnT as well as NT-proBNP. Adropin was also correlated with left ventricular systolic internal diameter (LVIDs) (r = 0.375, p = 0.045) and relative wall thickness (RWT) (r = -0.382, p = 0.034). Irisin was correlated with right ventricular diameter (RVd) (r = -0.363, p = 0.045). No correlations were found between irisin and adropin, and blood pressure (BP) measurements. CONCLUSIONS:Adropin could be a new candidate marker of cardiac dysfunction in HD patients. The cause of low levels of irisin found in HD patients is still unclear. These 2 myokines should be further investigated as potential prognostic markers of cardiac status in HD patients. 10.17219/acem/81538
    FNDC5/Irisin inhibits pathological cardiac hypertrophy. Yu Qing,Kou Wenxin,Xu Xu,Zhou Shunping,Luan Peipei,Xu Xiaopeng,Li Hailing,Zhuang Jianhui,Wang Jun,Zhao Yifan,Xu Yawei,Peng Wenhui Clinical science (London, England : 1979) Cardiac hypertrophy is a common pathophysiological process in various cardiovascular diseases, which still has no effective therapies. Irisin is a novel myokine mainly secreted by skeletal muscle and is believed to be involved in the regulation of energy metabolism. In the present study, we found that irisin expression was elevated in hypertrophic murine hearts and serum. Moreover, angiotension II-induced cardiomyocyte hypertrophy was attenuated after irisin administration and aggravated after irisin knockdown Next, we generated transverse aortic constriction (TAC)-induced cardiac hypertrophy murine model and found that cardiac hypertrophy and fibrosis were significantly attenuated with improved cardiac function assessed by echocardiography after irisin treatment. Mechanistically, we demonstrated that FNDC5 was cleaved into irisin, at least partially, in a disintegrin and metalloproteinase (ADAM) family-dependent manner. ADAM10 was the candidate enzyme responsible for the cleavage. Further, we found irisin treatment activated AMPK and subsequently inhibited activation of mTOR. AMPK inhibition ablated the protective role of irisin administration. In conclusion, we find irisin is secreted in an ADAM family-dependent manner, and irisin treatment improves cardiac function and attenuates pressure overload-induced cardiac hypertrophy and fibrosis mainly through regulating AMPK-mTOR signaling. 10.1042/CS20190016
    Irisin ameliorates septic cardiomyopathy via inhibiting DRP1-related mitochondrial fission and normalizing the JNK-LATS2 signaling pathway. Tan Ying,Ouyang Haichun,Xiao Xiaochan,Zhong Jiankai,Dong Maolong Cell stress & chaperones Irisin plays a protective effect in acute and chronic myocardial damage, but its role in septic cardiomyopathy is unclear. The aim of our study was to explore the in vivo and in vitro effects of irisin using an LPS-induced septic cardiomyopathy model. Our results demonstrated that irisin treatment attenuated LPS-mediated cardiomyocyte death and myocardial dysfunction. At the molecular level, LPS application was associated with mitochondrial oxidative injury, cardiomyocyte ATP depletion and caspase-related apoptosis activation. In contrast, the irisin treatment sustained mitochondrial function by inhibiting DRP1-related mitochondrial fission and the reactivation of mitochondrial fission impaired the protective action of irisin on inflammation-attacked mitochondria and cardiomyocytes. Additionally, we found that irisin modulated DRP1-related mitochondrial fission through the JNK-LATS2 signaling pathway. JNK activation and/or LATS2 overexpression abolished the beneficial effects of irisin on LPS-mediated mitochondrial stress and cardiomyocyte death. Altogether, our results illustrate that LPS-mediated activation of DRP1-related mitochondrial fission through the JNK-LATS2 pathway participates in the pathogenesis of septic cardiomyopathy. Irisin could be used in the future as an effective therapy for sepsis-induced myocardial depression because it corrects DRP1-related mitochondrial fission and normalizes the JNK-LATS2 signaling pathway. 10.1007/s12192-019-00992-2
    Irisin exerts a therapeutic effect against myocardial infarction via promoting angiogenesis. Liao Qiao,Qu Shuang,Tang Lu-Xun,Li Liang-Peng,He Duo-Fen,Zeng Chun-Yu,Wang Wei Eric Acta pharmacologica Sinica Irisin, a myokine, is cleaved from the extracellular portion of fibronectin domain-containing 5 protein in skeletal muscle and myocardium and secreted into circulation as a hormone during exercise. Irisin has been found to exert protective effects against lung and heart injuries. However, whether irisin influences myocardial infarction (MI) remains unclear. In this study we investigated the therapeutic effects of irisin in an acute MI model and its underlying mechanisms. Adult C57BL/6 mice were subjected to ligation of the left anterior descending coronary artery and treated with irisin for 2 weeks after MI. Cardiac function was assessed using echocardiography. We found that irisin administration significantly alleviated MI-induced cardiac dysfunction and ventricular dilation at 4 weeks post-MI. Irisin significantly reduced infarct size and fibrosis in post-MI hearts. Irisin administration significantly increased angiogenesis in the infarct border zone and decreased cardiomyocyte apoptosis, but did not influence cardiomyocyte proliferation. In human umbilical vein endothelial cells (HUVEC), irisin significantly increased the phosphorylation of ERK, and promoted the migration of HUVEC detected in wound-healing and transwell chamber migration assay. The effects of irisin were blocked by the ERK inhibitor U0126. In conclusion, irisin improves cardiac function and reduces infarct size in post-MI mouse heart. The therapeutic effect is associated with its pro-angiogenic function through activating ERK signaling pathway. 10.1038/s41401-019-0230-z
    Associations of Circulating Irisin Concentrations With Cardiometabolic Risk Factors Among Children Vary by Physical Activity or Sedentary Time Levels. Cai Li,Tan Minyi,Tan Weiqing,Zeng Xia,Wan Nianqing,Wong Stephen Heung-Sang,O'Reilly John,Sun Fenghua,Yang Jiewen,Chen Yajun Frontiers in endocrinology Whether irisin concentrations are associated with physical activity (PA) and sedentary time (ST) remains unknown. The role of irisin on cardiometabolic health among children has been contradictory and scarce. This study aimed to examine associations of PA and ST with irisin concentrations and relationships between irisin concentrations and cardiometabolic parameters among children. Additionally, we assessed the interaction between PA or ST and irisin concentrations on cardiometabolic parameters. Basing on a cross-sectional survey of 3,651 general children aged 7-12 years, 575 with different self-reported PA (moderate-vigorous intensity PA ≥ 60 min/day or <150 min/week) and ST (gender-, age-specific ST ≥ 75% or <25% percentile) levels were selected. PA and ST were assessed by the validated international physical activity questionnaires. Fasting blood glucose and lipid profile levels were measured with standard methods by biochemistry analyzer. Plasma irisin concentrations were measured by ELISA. The associations of PA and ST with circulating irisin concentrations were examined by linear regression. Linear regression analysis was also used to estimate associations of circulating irisin concentrations with cardiometabolic variables. Interactions between PA or ST and irisin concentrations on cardiometabolic parameters were calculated using multiple linear regression models with dichotomized factors (low PA and high PA; low ST and high ST). No significant association was observed between circulating irisin concentrations and habitual PA or ST. Irisin concentrations were negatively associated with body mass index (BMI) (β = -0.220), BMI z-score (β = -0.098), waist circumference (β = -0.621), diastolic blood pressure (DBP) (β = -0.561), and triglyceride (β = -0.019) in low PA subgroup, and negatively related to fasting blood glucose (β = -0.040) among high PA subgroup. Moreover, irisin concentrations were negatively associated with BMI (β = -0.157) and fasting blood glucose (β = -0.026) only in high ST subgroup (all < 0.05). We also observed a significant interaction between PA and irisin concentrations on BMI ( = 0.0350), BMI z-score ( = 0.0173), and DBP ( = 0.0068). In summary, irisin concentrations were not associated with habitual PA or ST in children. The negative associations of irisin concentrations with BMI, BMI z-score, and DBP were found only among children being inactive, implying that irisin may contribute to an improvement in health, especially among children with unhealthy lifestyles. 10.3389/fendo.2019.00549
    Serum irisin level in myocardial infarction patients with or without heart failure. Abd El-Mottaleb Nashwa A,Galal Heba M,El Maghraby Khaled M,Gadallah Aml I Canadian journal of physiology and pharmacology This study aimed to assess serum irisin level in myocardial infarction (MI) with or without heart failure (HF) and the possible relation between irisin and cardiac markers, tumor necrosis factor-α (TNF-α) and lipid profile. Eighty-six subjects were included (33 patients had MI, 33 patients had MI with HF, and 20 controls). Body mass index (BMI), waist/hip ratio (WHR), systolic and diastolic blood pressure (SBP and DBP), heart rate, and left ventricular ejection fraction (LVEF) were measured. Blood samples were withdrawn on admission for measuring irisin, cardiac markers, TNF-α, total cholesterol (TC), triglycerides (TGs), low-density lipoprotein-cholesterol concentration (LDL-C), and high-density lipoprotein-cholesterol concentration (HDL-C). Patients with MI and HF had reduced serum irisin, LVEF, and HDL-C and higher levels of BMI, WHR, SBP, DBP, troponin-I, creatine kinase-MB (CK-MB), TNF-α, TC, TGs, and LDL-C compared with control. Negative correlations were observed between irisin and BMI, WHR, SBP, DBP, troponin-I, CK-MB, TNF-α, TC, TGs, and LDL-C. However, positive association was noticed between irisin and LVEF and HDL-C. Irisin might be a useful biomarker in diagnosis of MI with or without HF. It could have anti-inflammatory and hypolipidemic effects. Further studies are needed to elucidate the role of irisin as a promising prophylactic or therapeutic agent in cardiovascular diseases. 10.1139/cjpp-2018-0736
    The Effects of Irisin on Nω-Nitro-L-arginine Methyl Ester Hydrochloride-Induced Hypertension in Rats Aydoğdu Nurettin,Yalçınkaya Yavuz Özlem,Taştekin Ebru,Tayfur Pınar,Kaya Oktay,Kandemir Nihayet Balkan medical journal Background:The cause of about 95% of hypertension, an important public health problem, is unknown. Intensive studies are underway to understand the physiopathology of hypertension. Irisin, a newly discovered hormone, has been reported to dilate vascular smooth muscle and lower blood pressure acutely. Aims:To investigate the effects of chronic irisin treatment on blood pressure and renal functions in a hypertension model established by nitric oxide synthase inhibition by treatment with Nω-nitro-L-arginine methyl ester hydrochloride. Study Design:Animal experimentation. Methods:Male Sprague−Dawley rats were divided into four groups (n=8). Control and irisin groups received an intravenous saline injection, hypertension and hypertension + irisin (hypertension + irisin) groups received 1.5 mg/100 g Nω-nitro-L-arginine methyl ester hydrochloride. Nω-nitro-L-arginine methyl ester hydrochloride (150 mg/L) was added to the drinking water of rats in groups hypertension and hypertension + irisin for three weeks. In the second week of the experiment, irisin (50 nmol/day) was given to rats in groups irisin and hypertension + irisin, and saline was administered to rats in groups control and hypertension for two weeks through subcutaneously placed osmotic minipumps. Blood pressure was measured by the tail-cuff plethysmography method. On the twenty-first day of the experiment, 24-hour urine, blood, and both kidneys of the rats were collected. Results:The hypertension group had elevated systolic, diastolic, and mean arterial blood pressure values compared with the control group, with decreased glutathione levels in tissue and serum, but an increase in serum oxidized glutathione level (p<0.05). Histopathologically, increased tubular injury, cast formation, glomerular sclerosis, and peritubular fibrosis levels were observed (p<0.05). Irisin treatment did not cause any significant change in blood pressure, renal functions, and injury scores. However, renal nitric oxide levels significantly increased, and endothelial nitric oxide synthase immunoreactivity was determined to be reduced (p<0.05). Conclusion:Treatment with chronic irisin at a physiological dose does not reduce blood pressure in an experimental model of hypertension. In different models of experimental hypertension, the effects of irisin administration at different doses and at different periods should be thoroughly investigated. 10.4274/balkanmedj.galenos.2019.2019.5.113
    Increased circulating levels of irisin are associated with cardiovascular risk factors in subjects with acromegaly. Calan Mehmet,Demirpence Mustafa Hormones (Athens, Greece) AIMS:Irisin, a peptide secreted from muscle and adipose tissues, is associated with insulin resistance as well as metabolic and cardiovascular diseases. Acromegaly is a rare disorder caused by overproduction of growth hormone (GH) and is associated with functional and structural differentiation of adipose and muscle tissues. Acromegalic subjects are also at risk of vascular diseases and metabolic dysfunctions. We aimed to determine the altered levels of irisin in subjects with active acromegaly and controlled acromegaly and in controls, and to ascertain whether there is an association between irisin and hormonal and cardiometabolic parameters. METHODS:We enrolled 40 subjects with active acromegaly, 30 subjects with controlled acromegaly, and 40 control subjects of matched age, gender, BMI, and occurrence of hypertension, diabetes, and metabolic syndrome distribution in the present cross-sectional study. Hormonal and metabolic parameters, carotid intima media thickness (cIMT), and epicardial fat thickness (EFT) of the subjects were evaluated. Irisin levels were measured using ELISA. RESULTS:Circulating levels of irisin were significantly higher in acromegalic subjects compared to both controlled acromegalic subjects and controls. Moreover, irisin levels were elevated in controlled acromegalic subjects compared to controls. Irisin displayed a positive correlation with insulin resistance, cIMT, EFT, BMI, GH, and insulin-like growth factor (IGF-1) in acromegalic subjects. Irisin levels were independently associated with cIMT and EFT according to multiple regression analyses. There was an independent relationship between irisin and IGF-1. CONCLUSIONS:Elevated irisin levels in acromegalic subjects were associated with cIMT and EFT, suggesting that irisin is a surrogate marker for cardiovascular risk in acromegalic subjects. 10.1007/s42000-019-00151-3
    Protective effects of irisin on hypoxia-reoxygenation injury in hyperglycemia-treated cardiomyocytes: Role of AMPK pathway and mitochondrial protection. Fan Jiamao,Zhu Qing,Wu Zhenhua,Ding Jiao,Qin Shuai,Liu Hui,Miao Pengfei Journal of cellular physiology Recent evidence has verified the cardioprotective actions of irisin in different diseases models. However, the beneficial action of irisin on hypoxia-reoxygenation (HR) injury under high glucose stress has not been described. Herein our research investigated the influence of irisin on HR-triggered cardiomyocyte death under high glucose stress. HR model was established in vitro under high glucose treatment. The results illuminated that HR injury augmented apoptotic ratio of cardiomyocyte under high glucose stress; this effect could be abolished by irisin via modulating mitochondrial function. Irisin treatment attenuated cellular redox stress, improved cellular ATP biogenetics, sustained mitochondria potential, and impaired mitochondrion-related cell death. At the molecular levels, irisin treatment activated the 5'-adenosine monophosphate-activated protein kinase (AMPK) pathway and the latter protected cardiomyocyte and mitochondria against HR injury under high glucose stress. Altogether, our results indicated a novel role of irisin in HR-treated cardiomyocyte under high glucose stress. Irisin-activated AMPK pathway and the latter sustained cardiomyocyte viability and mitochondrial function. 10.1002/jcp.29030