Reperfusion therapy with recombinant human relaxin-2 (Serelaxin) attenuates myocardial infarct size and NLRP3 inflammasome following ischemia/reperfusion injury via eNOS-dependent mechanism.
Valle Raleigh Juan,Mauro Adolfo G,Devarakonda Teja,Marchetti Carlo,He Jun,Kim Erica,Filippone Scott,Das Anindita,Toldo Stefano,Abbate Antonio,Salloum Fadi N
Aims:The preconditioning-like infarct-sparing and anti-inflammatory effects of the peptide hormone relaxin following ischemic injury have been studied in the heart. Whether reperfusion therapy with recombinant human relaxin-2, serelaxin, reduces myocardial infarct size and attenuates the subsequent NLRP3 inflammasome activation leading to further loss of functional myocardium following ischemia/reperfusion (I/R) injury is unknown. Methods and results:After baseline echocardiography, adult male wild-type C57BL or eNOS knockout mice underwent myocardial infarction (MI) by coronary artery ligation for 30 min followed by 24 h reperfusion. Mice were treated with either serelaxin (10 µg/kg; sc) or saline 1 h prior to ischemia or 5 min before reperfusion. In both pre-treatment and reperfusion therapy arms, serelaxin improved survival at 24 h post MI in wild-type mice (79% and 82%) as compared with controls (46% and 50%, P = 0.01), whereas there was no difference in survival between serelaxin- and saline-treated eNOS knockout mice. Moreover, serelaxin significantly reduced infarct size (64% and 67% reduction, P < 0.05), measured with TTC staining, and preserved LV fractional shortening (FS) and end-systolic diameter (LVESD) in wild-type mice as compared with controls (P < 0.05). Interestingly, caspase-1 activity in the heart tissue, a measure of inflammasome formation, was markedly reduced in serelaxin-treated wild-type mice compared with controls at 24 h post-MI in both treatment modalities (P < 0.05). Genetic deletion of eNOS abolished the infarct-sparing and anti-inflammatory effects of serelaxin as well as functional preservation. Serelaxin plasma levels assessed at 5 min and 1 h after treatment, using ELISA, approximated physiologic relaxin levels during pregnancy in mice and parallels that in humans. Conclusion:Serelaxin attenuates myocardial I/R injury and the subsequent caspase-1 activation via eNOS-dependent mechanism.
Platelet Serotonin Aggravates Myocardial Ischemia/Reperfusion Injury via Neutrophil Degranulation.
Mauler Maximilian,Herr Nadine,Schoenichen Claudia,Witsch Thilo,Marchini Timoteo,Härdtner Carmen,Koentges Christoph,Kienle Korbinian,Ollivier Véronique,Schell Maximilian,Dorner Ludwig,Wippel Christopher,Stallmann Daniela,Normann Claus,Bugger Heiko,Walther Paul,Wolf Dennis,Ahrens Ingo,Lämmermann Tim,Ho-Tin-Noé Benoît,Ley Klaus,Bode Christoph,Hilgendorf Ingo,Duerschmied Daniel
BACKGROUND:Platelets store large amounts of serotonin that they release during thrombus formation or acute inflammation. This facilitates hemostasis and modulates the inflammatory response. METHODS:Infarct size, heart function, and inflammatory cell composition were analyzed in mouse models of myocardial reperfusion injury with genetic and pharmacological depletion of platelet serotonin. These studies were complemented by in vitro serotonin stimulation assays of platelets and leukocytes in mice and men, and by measuring plasma serotonin levels and leukocyte activation in patients with acute coronary syndrome. RESULTS:Platelet-derived serotonin induced neutrophil degranulation with release of myeloperoxidase and hydrogen peroxide (HO) and increased expression of membrane-bound leukocyte adhesion molecule CD11b, leading to enhanced inflammation in the infarct area and reduced myocardial salvage. In patients hospitalized with acute coronary syndrome, plasmatic serotonin levels correlated with CD11b expression on neutrophils and myeloperoxidase plasma levels. Long-term serotonin reuptake inhibition-reported to protect patients with depression from cardiovascular events-resulted in the depletion of platelet serotonin stores in mice. These mice displayed a reduction in neutrophil degranulation and preserved cardiac function. In line, patients with depression using serotonin reuptake inhibition, presented with suppressed levels of CD11b surface expression on neutrophils and lower myeloperoxidase levels in blood. CONCLUSIONS:Taken together, we identify serotonin as a potent therapeutic target in neutrophil-dependent thromboinflammation during myocardial reperfusion injury.
Plasma exosomes protect the myocardium from ischemia-reperfusion injury.
Vicencio Jose M,Yellon Derek M,Sivaraman Vivek,Das Debashish,Boi-Doku Claire,Arjun Sapna,Zheng Ying,Riquelme Jaime A,Kearney Jessica,Sharma Vikram,Multhoff Gabriele,Hall Andrew R,Davidson Sean M
Journal of the American College of Cardiology
BACKGROUND:Exosomes are nanometer-sized vesicles released from cells into the blood, where they can transmit signals throughout the body. Shown to act on the heart, exosomes' composition and the signaling pathways they activate have not been explored. We hypothesized that endogenous plasma exosomes can communicate signals to the heart and provide protection against ischemia and reperfusion injury. OBJECTIVES:This study sought to isolate and characterize exosomes from rats and healthy volunteers, evaluate their cardioprotective actions, and identify the molecular mechanisms involved. METHODS:The exosome-rich fraction was isolated from the blood of adult rats and human volunteers and was analyzed by protein marker expression, transmission electron microscopy, and nanoparticle tracking analysis. This was then used in ex vivo, in vivo, and in vitro settings of ischemia-reperfusion, with the protective signaling pathways activated on cardiomyocytes identified using Western blot analyses and chemical inhibitors. RESULTS:Exosomes exhibited the expected size and expressed marker proteins CD63, CD81, and heat shock protein (HSP) 70. The exosome-rich fraction was powerfully cardioprotective in all tested models of cardiac ischemia-reperfusion injury. We identified a pro-survival signaling pathway activated in cardiomyocytes involving toll-like receptor (TLR) 4 and various kinases, leading to activation of the cardioprotective HSP27. Cardioprotection was prevented by a neutralizing antibody against a conserved HSP70 epitope expressed on the exosome surface and by blocking TLR4 in cardiomyocytes, identifying the HSP70/TLR4 communication axis as a critical component in exosome-mediated cardioprotection. CONCLUSIONS:Exosomes deliver endogenous protective signals to the myocardium by a pathway involving TLR4 and classic cardioprotective HSPs.
Connexin43 and Myocardial Ischemia-Reperfusion Injury.
Zu Lingyun,Wen Ningxin,Liu Changjie,Zhao Mingming,Zheng Lemin
Cardiovascular & hematological disorders drug targets
BACKGROUND:Recently, the treatment and prevention of ischemic cardiomyopathy is one of the emerging research topics in the cardiovascular field. Gap junction is the basic structure of cardiac electrophysiology. Connexin is the basic unit of gap junctions. Connexin43(CX43) is the most abundant member of Cx family in the heart, the normal expression of Cx43 is important for heart development, electrically coupled cardiomyocytes activities and coordination of myocardial function. The connection between Cx43 and myocardial ischemia/reperfusion or reperfusion injury has become the focus of current research. METHODS:We undertook a structured search of bibliographic database for peer-reviewed research literature using a focused review question and inclusion/exclusion criteria. The quality of retrieved papers was appraised using standard tools. The characteristics of screened papers were described, and a deductive qualitative content analysis methodology was applied to analyze the interventions and findings of included studies using a conceptual framework. RESULTS:Twenty-one papers were included in the review, eight papers outlined the relationship of Cx43 and reperfusion arrhythmias. Eight papers pointed out the effect on the infarct size of Cx43. CONCLUSION:The findings of this review confirm that Cx43 is the most abundant member of Cx family in the heart and is vital for myocardial protection during ischemia/reperfusion process and for ischemia/reperfusion injury. Many of its mechanism are still not very clear and require future research in the future.
Platelets, diabetes and myocardial ischemia/reperfusion injury.
Russo Isabella,Penna Claudia,Musso Tiziana,Popara Jasmin,Alloatti Giuseppe,Cavalot Franco,Pagliaro Pasquale
Mechanisms underlying the pathogenesis of ischemia/reperfusion injury are particularly complex, multifactorial and highly interconnected. A complex and entangled interaction is also emerging between platelet function, antiplatelet drugs, coronary diseases and ischemia/reperfusion injury, especially in diabetic conditions. Here we briefly summarize features of antiplatelet therapy in type 2 diabetes (T2DM). We also treat the influence of T2DM on ischemia/reperfusion injury and how anti-platelet therapies affect post-ischemic myocardial damage through pleiotropic properties not related to their anti-aggregating effects. miRNA-based signature associated with T2DM and its cardiovascular disease complications are also briefly considered. Influence of anti-platelet therapies and different effects of healthy and diabetic platelets on ischemia/reperfusion injury need to be further clarified in order to enhance patient benefits from antiplatelet therapy and revascularization. Here we provide insight on the difficulty to reduce the cardiovascular risk in diabetic patients and report novel information on the cardioprotective role of widely used anti-aggregant drugs.
The Dual Role of Inducible Nitric Oxide Synthase in Myocardial Ischemia/Reperfusion Injury: Friend or Foe?
Yu Xin,Ge Liang,Niu Liang,Lian Xin,Ma Haichun,Pang Lei
Oxidative medicine and cellular longevity
Nitric oxide synthases (NOSs) are a family of enzymes that are responsible for the synthesis of nitric oxide (NO) from the amino acid L-arginine in the body. Among the three key NOSs, the expression of inducible NOS (iNOS) can only be induced by inflammatory stimuli and contribute to the large amount of NO production. iNOS-derived NO plays an important role in various physiological and pathophysiological conditions, including the ischemic heart disease. Nowadays, the development of specific iNOS inhibitors and the availability of iNOS knockout mice have provided substantial evidence to support the role of iNOS/NO signaling in the myocardium. Nevertheless, the role of iNOS/NO signaling in the myocardial ischemic reperfusion injury is very complex and highly perplexing; both detrimental and beneficial effects of iNOS have been described. Thus, this review will aim at providing basic insights into the current progress of the role of iNOS in myocardial ischemia reperfusion injury. A better understanding of the dual role of iNOS in details may help facilitate the development of more effective therapies for the management of ischemic heart diseases.
Platelet Contributions to Myocardial Ischemia/Reperfusion Injury.
Schanze Nancy,Bode Christoph,Duerschmied Daniel
Frontiers in immunology
Obstruction of a coronary artery causes ischemia of heart tissue leading to myocardial infarction. Prolonged oxygen deficiency provokes tissue necrosis, which can result in heart failure and death of the patient. Therefore, restoration of coronary blood flow (reperfusion of the ischemic area) by re-canalizing the affected vessel is essential for a better patient outcome. Paradoxically, sudden reperfusion also causes tissue injury, thereby increasing the initial ischemic damage despite restoration of blood flow (=ischemia/reperfusion injury, IRI). Myocardial IRI is a complex event that involves various harmful mechanisms (e.g., production of reactive oxygen species and local increase in calcium ions) as well as inflammatory cells and signals like chemokines and cytokines. An involvement of platelets in the inflammatory reaction associated with IRI was discovered several years ago, but the underlying mechanisms are not yet fully understood. This mini review focusses on platelet contributions to the intricate picture of myocardial IRI. We summarize how upregulation of platelet surface receptors and release of immunomodulatory mediators lead to aggravation of myocardial IRI and subsequent cardiac damage by different mechanisms such as recruitment and activation of immune cells or modification of the cardiac vascular endothelium. In addition, evidence for cardioprotective roles of distinct platelet factors during IRI will be discussed.
Heat shock protein 70: A promising therapeutic target for myocardial ischemia-reperfusion injury.
Song Yan-Jun,Zhong Chong-Bin,Wang Xian-Bao
Journal of cellular physiology
Acute myocardial infarction is a major cause of death worldwide. The most important therapy for limiting ischemic injury and infarct size is timely and efficient myocardial reperfusion treatment, which may instead induce cardiomyocyte necrosis due to myocardial ischemia-reperfusion (I/R) injury. Heat shock protein 70 (HSP70), a stress-inducible protein, is overexpressed during myocardial I/R. The induced HSP70 is shown to regulate several intracellular proteins (e.g., transcription factors, enzymes, and apoptosis-related proteins) and signaling pathways (e.g., c-Jun N-terminal kinase pathway and extracellular-signal-regulated kinase 1/2 pathway), forming a complicated network that contributes to reducing reactive oxygen species accumulation, improving calcium homeostasis, inhibiting cellular apoptosis, thereby enhancing the stress adaption of myocardium to I/R injury. In addition, the extracellular HSP70, which is released from injured cardiomyocytes during I/R, acts as a proinflammatory mediator that results in cell death, while the intracellular HSP70 exerts antiinflammatory effects by suppressing proinflammatory signaling pathways. Notably, HSP70 is induced and contributes to the cardioprotection in several types of preconditioning and postconditioning. Meanwhile, it is shown that the cardioprotective effectiveness of preconditioning-induced HSP70 (e.g., hyperthermia preconditioning-induced HSP70) can be impaired by certain pathological conditions, such as hyperlipidemia and hyperglycemia. Thus, we highlight the widespread cardioprotective involvement of HSP70 in preconditioning and postconditioning and elucidate how HSP70-mediated cardioprotection is impaired in these pathological conditions. Furthermore, several therapeutic potentials of HSP70 against myocardial I/R injury and potential directions for future studies are also provided in this review.
Progress in Therapies for Myocardial Ischemia Reperfusion Injury.
Chi Hong-Jie,Chen Mu-Lei,Yang Xin-Chun,Lin Xiang-Min,Sun Hao,Zhao Wen-Shu,Qi Dan,Dong Jia-Lu,Cai Jun
Current drug targets
BACKGROUND:Experimental studies of acute myocardial infarction have revealed that up to half of the final infarct size may be due to reperfusion injury rather than the initial ischemic incident. Research over the past three decades has deepened our understanding of the molecular mechanisms underlying ischemic reperfusion injury and several therapeutic strategies to decrease the incidence and severity of reperfusion injury have been explored. OBJECTIVE:To discuss the promising therapies and future perspectives on methods to attenuate myocardial reperfusion injury. RESULTS:Existing therapies that address reperfusion can be divided into two major groups comprising nonpharmacological and pharmacological interventions. Myriad pharmacological and nonpharmacological approaches to reduce lethal reperfusion injury have been employed. Although many initial clinical studies were negative, more recent proof-of-concept clinical trials are promising. To date, the most encouraging results are with ischemic postconditioning, remote ischemic preconditioning, ANP, adenosine, cyclosporine and exenatide. CONCLUSION:Studies demonstrate that nonpharmacological and pharmacological conditioning can be used together as part of a multifaceted approach to improve clinical outcomes in patients with ischemic heart disease.
Mitochondrial bioenergetics and cardiolipin alterations in myocardial ischemia-reperfusion injury: implications for pharmacological cardioprotection.
Paradies Giuseppe,Paradies Valeria,Ruggiero Francesca Maria,Petrosillo Giuseppe
American journal of physiology. Heart and circulatory physiology
Mitochondrial dysfunction plays a central role in myocardial ischemia-reperfusion (I/R) injury. Increased reactive oxygen species production, impaired electron transport chain activity, aberrant mitochondrial dynamics, Ca overload, and opening of the mitochondrial permeability transition pore have been proposed as major contributory factors to mitochondrial dysfunction during myocardial I/R injury. Cardiolipin (CL), a mitochondria-specific phospholipid, plays a pivotal role in multiple mitochondrial bioenergetic processes, including respiration and energy conversion, in mitochondrial morphology and dynamics as well as in several steps of the apoptotic process. Changes in CL levels, species composition, and degree of oxidation may have deleterious consequences for mitochondrial function with important implications in a variety of pathophysiological conditions, including myocardial I/R injury. In this review, we focus on the role played by CL alterations in mitochondrial dysfunction in myocardial I/R injury. Pharmacological strategies to prevent myocardial injury during I/R targeting mitochondrial CL are also examined.
Progression in attenuating myocardial reperfusion injury: an overview.
Bernink F J P,Timmers L,Beek A M,Diamant M,Roos S T,Van Rossum A C,Appelman Y
International journal of cardiology
Reperfusion by means of percutaneous coronary intervention or thrombolytic therapy is the most effective treatment for acute myocardial infarction, markedly reducing mortality and morbidity. Reperfusion however induces necrotic and apoptotic damages to cardiomyocytes, that were viable prior to reperfusion, a process called lethal reperfusion injury. This process, consisting of many single processes, may be responsible of up to half of the final infarct size. A myriad of therapies as an adjunct to reperfusion have been studied with the purpose to attenuate reperfusion injury. The majority of these studies have been disappointing or contradicting, but recent proof-of-concept trials show that reperfusion injury still is a legitimate target. This overview will discuss these trials, the progression in attenuating myocardial reperfusion injury, promising therapies, and future perspectives.
The role of secretory phospholipases as therapeutic targets for the treatment of myocardial ischemia reperfusion injury.
Ravindran Sriram,Kurian Gino A
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Myocardial reperfusion injury is a consequence of restoration of blood flow post ischemia. It is a complex process involving an acute inflammatory response activated by cytokines, chemokines, growth factors, and mediated by free radicals, calcium overload leading to mitochondrial dysfunction. Secretory phospholipases (sPLA2) are a group of pro-inflammatory molecules associated with diseases such as atherosclerosis, which increase the risk of reperfusion injury. This acute response leads to breakdown of phospholipids such as cardiolipin, found in the mitochondrial inner membrane, leading to disruption of energy producing enzymes of the electron transport chain. Thus the activation of secretory phospholipases has a direct link to the vascular occlusion and arrhythmia observed in myocardial reperfusion injury. Therapeutic agents targeting sPLA2 are under human trials and many are in the preclinical phase. This article reviews the pathological effects of various groups of secretory phospholipases (I, II, V and X) implicated in myocardial ischemia reperfusion injury and the phospholipase inhibitors under development. Considering the fact that human trials in this class of drugs is limited, sPLA2 as a potential target for drug development is emphasized.
The Lectin Pathway of Complement in Myocardial Ischemia/Reperfusion Injury-Review of Its Significance and the Potential Impact of Therapeutic Interference by C1 Esterase Inhibitor.
Panagiotou Anneza,Trendelenburg Marten,Osthoff Michael
Frontiers in immunology
Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality in modern medicine. Early reperfusion accomplished by primary percutaneous coronary intervention is pivotal for reducing myocardial damage in ST elevation AMI. However, restoration of coronary blood flow may paradoxically trigger cardiomyocyte death secondary to a reperfusion-induced inflammatory process, which may account for a significant proportion of the final infarct size. Unfortunately, recent human trials targeting myocardial ischemia/reperfusion (I/R) injury have yielded disappointing results. In experimental models of myocardial I/R injury, the complement system, and in particular the lectin pathway, have been identified as major contributors. In line with this, C1 esterase inhibitor (C1INH), the natural inhibitor of the lectin pathway, was shown to significantly ameliorate myocardial I/R injury. However, the hypothesis of a considerable augmentation of myocardial I/R injury by activation of the lectin pathway has not yet been confirmed in humans, which questions the efficacy of a therapeutic strategy solely aimed at the inhibition of the lectin pathway after human AMI. Thus, as C1INH is a multiple-action inhibitor targeting several pathways and mediators simultaneously in addition to the lectin pathway, such as the contact and coagulation system and tissue leukocyte infiltration, this may be considered as being advantageous over exclusive inhibition of the lectin pathway. In this review, we summarize current concepts and evidence addressing the role of the lectin pathway as a potent mediator/modulator of myocardial I/R injury in animal models and in patients. In addition, we focus on the evidence and the potential advantages of using the natural inhibitor of the lectin pathway, C1INH, as a future therapeutic approach in AMI given its ability to interfere with several plasmatic cascades. Ameliorating myocardial I/R injury by targeting the complement system and other plasmatic cascades remains a valid option for future therapeutic interventions.
The protective role of curcumin in myocardial ischemia-reperfusion injury.
Mokhtari-Zaer Amin,Marefati Narges,Atkin Stephen L,Butler Alexandra E,Sahebkar Amirhossein
Journal of cellular physiology
Coronary artery disease (CAD) is a well-known pathological condition that is characterized by high morbidity and mortality. The main pathological manifestation of CAD is myocardial injury due to ischemia-reperfusion (I-R). Currently, no efficacious treatment of protecting the heart against myocardial I-R exists. Hence, it is necessary to discover or develop novel strategies to prevent myocardial-reperfusion injury to improve clinical outcomes in patients with CAD. A large body of experimental evidence supports cardioprotective properties of curcumin and the ability of this phytochemical to modify some cardiovascular risk factors. However, the detailed effects of curcumin in myocardial I-R injury are still unclear and there is a lack of evidence concerning which curcumin regimen may be ideal for myocardial I-R injury. This paper presents a brief review of the pathophysiology of myocardial I-R injury and the mechanisms of action of curcumin in reducing myocardial I-R injury.
Contribution of apoptosis in myocardial reperfusion injury and loss of cardioprotection in diabetes mellitus.
Badalzadeh Reza,Mokhtari Behnaz,Yavari Raana
The journal of physiological sciences : JPS
Ischemic heart disease is one of the major causes of death worldwide. Ischemia is a condition in which blood flow of the myocardium declines, leading to cardiomyocyte death. However, reperfusion of ischemic regions decreases the rate of mortality, but it can also cause later complications. In a clinical setting, ischemic heart disease is always coincident with other co-morbidities such as diabetes. The risk of heart disease increases 2-3 times in diabetic patients. Apoptosis is considered to be one of the main pathophysiological mechanisms of myocardial ischemia-reperfusion injury. Diabetes can disrupt the anti-apoptotic intracellular signaling cascades involved in myocardial protection. Therefore, targeting these changes may be an effective cardioprotective approach in the diabetic myocardium against ischemia-reperfusion injury. In this article, we review the interaction of diabetes with the pathophysiology of myocardial ischemia-reperfusion injury, focusing on the contribution of apoptosis in this context, and then discuss the alterations of pro-apoptotic or anti-apoptotic pathways probably responsible for the loss of cardioprotection in diabetes.
The Role of Non-coding RNAs in Ischemic Myocardial Reperfusion Injury.
Siebert Vince,Allencherril Joseph,Ye Yumei,Wehrens Xander H T,Birnbaum Yochai
Cardiovascular drugs and therapy
MicroRNAs (miRNA) are non-coding RNAs that regulate gene expression in up to 90% of the human genome through interactions with messenger RNA (mRNA). The expression of miRNAs varies and changes in diseased and healthy states, including all stages of myocardial ischemia-reperfusion and subsequent ischemia-reperfusion injury (IRI). These changes in expression make miRNAs an attractive potential therapeutic target. Herein, we review the differences in miRNA expression prior to ischemia (including remote ischemic conditioning and ischemic pre-conditioning), the changes during ischemia-reperfusion, and the changes in miRNA expression after IRI, with an emphasis on inflammatory and fibrotic pathways. Additionally, we review the effects of manipulating the levels of certain miRNAs on changes in infarct size, inflammation, remodeling, angiogenesis, and cardiac function after either ischemia-reperfusion or permanent coronary ligation. Levels of target miRNA can be increased using molecular mimics ("agomirs"), or can be decreased by using "antagomirs" which are antisense molecules that act to bind and thus inactivate the target miRNA sequence. Other non-coding RNAs, including long non-coding RNAs and circular RNAs, also regulate gene expression and have a role in the regulation of IRI pathways. We review the mechanisms and downstream effects of the miRNAs that have been studied as therapy in both permanent coronary ligation and ischemia-reperfusion models.