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    Cellular signalling crosstalk between different cardiac cell populations - An insight into the role of exosomes in the heart diseases and therapy. Nguyen Binh Yen,Azam Tayyiba,Wang Xin American journal of physiology. Heart and circulatory physiology Exosomes are a subgroup of extracellular bilayer membrane nanovesicles that are enriched in a variety of bioactive lipids, receptors, transcription factors, surface proteins, DNA and noncoding RNAs. They have been well-recognised to play essential roles in mediating intercellular signalling by delivering bioactive molecules from host cells to regulate the physiological processes of recipient cells. In the context of heart diseases, accumulating studies have indicated that exosome-carried cellular proteins and noncoding RNA derived from different types of cardiac cells, including cardiomyocytes, fibroblasts, endothelial cells, immune cells, adipocytes and resident stem cells have pivotal roles in cardiac remodelling under disease conditions such as cardiac hypertrophy, diabetic cardiomyopathy and MI. In addition, exosomal contents derived from stem cells have been shown to be beneficial for regenerative potential of the heart. In this review, we will discuss current understanding of the role of exosomes in cardiac communication, with a focus on cardiovascular pathophysiology and perspectives for their potential uses as cardiac therapies. 10.1152/ajpheart.00718.2020
    Exosomes derived from cardiac parasympathetic ganglionic neurons inhibit apoptosis in hyperglycemic cardiomyoblasts. Singla Reetish,Garner Kaley H,Samsam Mohtashem,Cheng Zixi,Singla Dinender K Molecular and cellular biochemistry Diabetic cardiomyopathy is known to involve two forms of cardiac cell death: apoptosis and necrosis. However, it remains unknown whether hyperglycemia-induced apoptosis in the H9c2 cell culture system is inhibited by parasympathetic ganglionic neurons (PGN) derived exosomes (exos). We isolated PGN and sympathetic ganglionic neurons (SGN) from the right stellate ganglion in rats, and derived exos from these sources. H9c2 cells were divided into 4 groups: (1) Control, (2) H9c2 + Glucose (100 mmol/L), (3) H9c2 + Glucose + PGN-exos, and (4) H9c2 + Glucose + SGN-exos. We determined cell proliferation and viability with an MTT assay kit, and assessed apoptotic cell death with TUNEL staining and ELISA. Data were further confirmed by analyzing the presence of pro-apoptotic proteins Caspase-3 and Bax, and anti-apoptotic protein Bcl-2. Glucose exposed H9c2 cells significantly reduced cell viability, which was improved by PGN-exos, but not by SGN-exos. Furthermore, increased apoptosis in hyperglycemia in H9c2 cells was confirmed with TUNEL staining and cell death ELISA which demonstrated significantly (p < 0.05) reduction with PGN-exos treatment, but not with SGN-exos. Moreover, high expression of pro-apoptotic proteins Caspase-3 and Bax was reduced following treatment with PGN-exos; however, SGN-exos were unable to reduce the expression. Significantly reduced anti-apoptotic protein Bcl-2 following glucose treatment was improved with PGN-exos. Therefore, our data suggest that hyperglycemia induces apoptosis in H9c2 cells and decreases cell viability, and that PGN-exos are able to inhibit apoptosis, improve cell viability, and restore levels of anti-apoptotic protein Bcl-2. 10.1007/s11010-019-03604-w
    Pathologic function and therapeutic potential of exosomes in cardiovascular disease. Ailawadi Shaina,Wang Xiaohong,Gu Haitao,Fan Guo-Chang Biochimica et biophysica acta The heart is a very complex conglomeration of organized interactions between various different cell types that all aid in facilitating myocardial function through contractility, sufficient perfusion, and cell-to-cell reception. In order to make sure that all features of the heart work effectively, it is imperative to have a well-controlled communication system among the different types of cells. One of the most important ways that the heart regulates itself is by the use of extracellular vesicles, more specifically, exosomes. Exosomes are types of nano-vesicles, naturally released from living cells. They are believed to play a critical role in intercellular communication through the means of certain mechanisms including direct cell-to-cell contact, long-range signals as well as electrical and extracellular chemical molecules. Exosomes contain many unique features like surface proteins/receptors, lipids, mRNAs, microRNAs, transcription factors and other proteins. Recent studies indicate that the exosomal contents are highly regulated by various stress and disease conditions, in turn reflective of the parent cell status. At present, exosomes are well appreciated to be involved in the process of tumor and infection disease. However, the research on cardiac exosomes is just emerging. In this review, we summarize recent findings on the pathologic effects of exosomes on cardiac remodeling under stress and disease conditions, including cardiac hypertrophy, peripartum cardiomyopathy, diabetic cardiomyopathy and sepsis-induced cardiovascular dysfunction. In addition, the cardio-protective effects of stress-preconditioned exosomes and stem cell-derived exosomes are also summarized. Finally, we discuss how to epigenetically reprogram exosome contents in host cells which makes them beneficial for the heart. 10.1016/j.bbadis.2014.10.008
    New Molecular Insights of Insulin in Diabetic Cardiomyopathy. Westermeier Francisco,Riquelme Jaime A,Pavez Mario,Garrido Valeria,Díaz Ariel,Verdejo Hugo E,Castro Pablo F,García Lorena,Lavandero Sergio Frontiers in physiology Type 2 diabetes mellitus (T2DM) is a highly prevalent disease worldwide. Cardiovascular disorders generated as a consequence of T2DM are a major cause of death related to this disease. Diabetic cardiomyopathy (DCM) is characterized by the morphological, functional and metabolic changes in the heart produced as a complication of T2DM. This cardiac disorder is characterized by constant high blood glucose and lipids levels which eventually generate oxidative stress, defective calcium handling, altered mitochondrial function, inflammation and fibrosis. In this context, insulin is of paramount importance for cardiac contractility, growth and metabolism and therefore, an impaired insulin signaling plays a critical role in the DCM development. However, the exact pathophysiological mechanisms leading to DCM are still a matter of study. Despite the numerous questions raised in the study of DCM, there have also been important findings, such as the role of micro-RNAs (miRNAs), which can not only have the potential of being important biomarkers, but also therapeutic targets. Furthermore, exosomes also arise as an interesting variable to consider, since they represent an important inter-cellular communication mechanism and therefore, they may explain many aspects of the pathophysiology of DCM and their study may lead to the development of therapeutic agents capable of improving insulin signaling. In addition, adenosine and adenosine receptors (ARs) may also play an important role in DCM. Moreover, the possible cross-talk between insulin and ARs may provide new strategies to reverse its defective signaling in the diabetic heart. This review focuses on DCM, the role of insulin in this pathology and the discussion of new molecular insights which may help to understand its underlying mechanisms and generate possible new therapeutic strategies. 10.3389/fphys.2016.00125
    Exosomes in Diabetic Cardiomyopathy: The Next-Generation Therapeutic Targets? Sahoo Susmita,Emanueli Costanza Diabetes 10.2337/dbi16-0041
    Effects and mechanism of glucagon-like peptide-1 on injury of rats cardiomyocytes induced by hypoxia-reoxygenation. Xie Yun,Wang Shao-xin,Sha Wei-wei,Zhou Xue,Wang Wei-lin,Han Li-pin,Li Dai-qing,Yu De-min Chinese medical journal BACKGROUND:Although the insulinotropic role of glucagon-like peptide-1 (GLP-1) in type 2 diabetes mellitus has been substantiated, its role in cardioprotection remains largely unknown. This study aimed to determine the effects of GLP-1 on injury of rats cardiac myocytes induced by hypoxia-reoxygenation (H/R) and the possible mechanisms. METHODS:The cultured neonatal rats cardiac myocytes were randomly divided into seven groups: the normal control group, the H/R group, the GLP-1 + H/R group, the GLP-1 + H/R + UO126 (the p42/44 mitogen-activated protein kinase (MAPK) inhibitor) group, the GLP-1 + H/R + LY294002 (phosphatidylinositol 3-kinase (PI3K) inhibitor) group, the H/R + UO126 group, and the H/R + LY294002 group. The lactate dehydrogenase (LDH) activity, apoptosis rate of cardiac myocytes, and caspase-3 activity were detected after the injury of H/R. RESULTS:Compared with the normal control group, the activity of LDH, cardiac myocyte apoptosis rate, and caspase-3 activity all increased significantly in the H/R group (P < 0.01). Compared with the H/R group, these three indices all decreased in the H/R + GLP-1 group (P < 0.01). However, the changes of LDH activity, apoptosis rate, and caspase-3 activity were inhibited by LY294002 and UO126 respectively. CONCLUSIONS:GLP-1 can directly act on cardiac myocytes and protect them from H/R injury mainly by inhibiting their apoptosis. Its mechanism may be through the PI3K-Akt pathway and the MAPK signaling pathway.
    GLP-1 and cardioprotection: from bench to bedside. Ravassa Susana,Zudaire Amaia,Díez Javier Cardiovascular research During myocardial infarction (MI), a variety of mechanisms contribute to the activation of cell death processes in cardiomyocytes, determining the final MI size, subsequent mortality, and post-MI remodelling. The deleterious mechanisms accompanying the ischaemic and reperfusion phases in MI include deprivation of oxygen, nutrients, and survival factors, accumulation of waste products, generation of oxygen free radicals, calcium overload, neutrophil infiltration of the ischaemic area, depletion of energy stores, and opening of the mitochondrial permeability transition pore, all of which contribute to the activation of apoptosis and necrosis in cardiomyocytes. During the last few years, glucagon-like peptide-1 (GLP-1) (7-36)-based therapeutic strategies have been incorporated into the treatment of patients with type 2 diabetes mellitus. Cytoprotection is among the pleiotropic actions described for GLP-1 in different cell types, including cardiomyocytes. This paper reviews the most relevant experimental and clinical studies that have contributed to a better understanding of the molecular mechanisms and intracellular pathways involved in the cardioprotection induced by GLP-1, analysing in depth its potential role as a therapeutic target in the ischaemic and reperfused myocardium as well as in other pathologies that are associated with myocardial remodelling and heart failure. 10.1093/cvr/cvs123
    Overexpression of microRNA-216a-3p Accelerates the Inflammatory Response in Cardiomyocytes in Type 2 Diabetes Mellitus by Targeting IFN-α2. Liu Xiaomeng,Zhang Yusong,Liang Hongwei,Xu Yanchao Frontiers in endocrinology Type 2 diabetes mellitus (T2DM) is a chronic, hyperglycemia-associated, metabolic disorder. Heart disease is a major complication of T2DM. The present study aimed to explore the effects of miR-216a-3p on cardiomyocyte proliferation, apoptosis, and inflammation in T2DM through the Toll-like receptor (TLR) pathway involving interferon-α2 (IFN-α2) mediation. T2DM was induced in rats by a high-fat diet, in combination with an intraperitoneal injection of low-dose streptozotocin. ELISAs were conducted to measure inflammatory-related factors in serum. Next, isolated cardiomyocytes were used in loss- and gain-of-function experiments, followed by MTT and flow cytometry assays, conducted to evaluate cell proliferation, cell cycle, and apoptosis. Our results revealed an increase in the inflammatory response in T2DM rat models, accompanied by significantly increased expression of miR-216a-3p and TLR pathway-related genes. However, a decrease in the expression of IFN-α2 was observed. Moreover, the presence of an miR-216a-3p inhibitor and si-IFN-α2 increased the expression of TLR pathway-related genes and cell apoptosis, whereas cell proliferation was significantly decreased in the cardiomyocytes. We found that in T2DM, miR-216a-3p inhibited the proliferation and enhanced the apoptosis of cardiomyocytes and generated an inflammatory response through activation of the TLR pathway and targeting of IFN-α2. 10.3389/fendo.2020.522340
    Upregulation of PKR pathway mediates glucolipotoxicity induced diabetic cardiomyopathy in vivo in wistar rats and in vitro in cultured cardiomyocytes. Mangali Sureshbabu,Bhat Audesh,Jadhav Kirtikumar,Kalra Jaspreet,Sriram Dharmarajan,Vamsi Krishna Venuganti Venkata,Dhar Arti Biochemical pharmacology AIMS:Protein Kinase R (PKR) plays a key role in inflammation and insulin resistance. Cytokines, high fat diet, infection and various stress signals can activate PKR. However, the functional significance of PKR in diabetic cardiomyopathy (DCM) is not explored so far. Thus the aim of the present study was to investigate the role of PKR in DCM in vivo in a rat model of DCM and underlying molecular mechanism. METHODS AND RESULTS:DCM was induced in Wistar rats by recipe of high fat diet and single injection of streptozotocin. Vital parameters were measured by non-invasive BP apparatus. Morphology, fibrosis and protein expression in heart was done by haematoxylin & eosin staining, masson's trichome/sirius red staining and western blotting respectively. For molecular mechanism studies, PKR gene silencing was done in cultured H9C2 cardiomyocytes and effect was observed in the presence of high glucose and high fat. Significant upregulation of PKR along with increase in cardiac biomarkers, decreased systolic and diastolic cardiac functions, oxidative stress, inflammatory markers, markers of fibrosis, enhanced cell death and AGEs' was observed in DCM disease model. Moreover, selective inhibition of PKR alleviated cardiac dysfunction, fibrosis, oxidative stress, inflammation and cell death. Additionally knockdown of PKR attenuated glucolipotoxicty-induced markers of inflammation, oxidative stress and apoptosis in cultured H9C2 cardiomyocytes. CONCLUSION:Our present study reports for the first time that inhibition of PKR may have great therapeutic potential in the treatment of DCM by attenuating inflammation, oxidative stress, apoptosis and fibrosis. 10.1016/j.bcp.2020.113948
    Rac1 is required for cardiomyocyte apoptosis during hyperglycemia. Shen E,Li Yanwen,Li Ying,Shan Limei,Zhu Huaqing,Feng Qingping,Arnold J Malcolm O,Peng Tianqing Diabetes OBJECTIVE:Hyperglycemia induces reactive oxygen species (ROS) and apoptosis in cardiomyocytes, which contributes to diabetic cardiomyopathy. The present study was to investigate the role of Rac1 in ROS production and cardiomyocyte apoptosis during hyperglycemia. RESEARCH DESIGN AND METHODS:Mice with cardiomyocyte-specific Rac1 knockout (Rac1-ko) were generated. Hyperglycemia was induced in Rac1-ko mice and their wild-type littermates by injection of streptozotocin (STZ). In cultured adult rat cardiomyocytes, apoptosis was induced by high glucose. RESULTS:The results showed a mouse model of STZ-induced diabetes, 7 days of hyperglycemia-upregulated Rac1 and NADPH oxidase activation, elevated ROS production, and induced apoptosis in the heart. These effects of hyperglycemia were significantly decreased in Rac1-ko mice or wild-type mice treated with apocynin. Interestingly, deficiency of Rac1 or apocynin treatment significantly reduced hyperglycemia-induced mitochondrial ROS production in the heart. Deficiency of Rac1 also attenuated myocardial dysfunction after 2 months of STZ injection. In cultured cardiomyocytes, high glucose upregulated Rac1 and NADPH oxidase activity and induced apoptotic cell death, which were blocked by overexpression of a dominant negative mutant of Rac1, knockdown of gp91(phox) or p47(phox), or NADPH oxidase inhibitor. In type 2 diabetic db/db mice, administration of Rac1 inhibitor, NSC23766, significantly inhibited NADPH oxidase activity and apoptosis and slightly improved myocardial function. CONCLUSIONS:Rac1 is pivotal in hyperglycemia-induced apoptosis in cardiomyocytes. The role of Rac1 is mediated through NADPH oxidase activation and associated with mitochondrial ROS generation. Our study suggests that Rac1 may serve as a potential therapeutic target for cardiac complications of diabetes. 10.2337/db08-0617