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    Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity. Jia Guanghong,Hill Michael A,Sowers James R Circulation research Heart failure and related morbidity and mortality are increasing at an alarming rate, in large part, because of increases in aging, obesity, and diabetes mellitus. The clinical outcomes associated with heart failure are considerably worse for patients with diabetes mellitus than for those without diabetes mellitus. In people with diabetes mellitus, the presence of myocardial dysfunction in the absence of overt clinical coronary artery disease, valvular disease, and other conventional cardiovascular risk factors, such as hypertension and dyslipidemia, has led to the descriptive terminology, diabetic cardiomyopathy. The prevalence of diabetic cardiomyopathy is increasing in parallel with the increase in diabetes mellitus. Diabetic cardiomyopathy is initially characterized by myocardial fibrosis, dysfunctional remodeling, and associated diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure. Impaired cardiac insulin metabolic signaling, mitochondrial dysfunction, increases in oxidative stress, reduced nitric oxide bioavailability, elevations in advanced glycation end products and collagen-based cardiomyocyte and extracellular matrix stiffness, impaired mitochondrial and cardiomyocyte calcium handling, inflammation, renin-angiotensin-aldosterone system activation, cardiac autonomic neuropathy, endoplasmic reticulum stress, microvascular dysfunction, and a myriad of cardiac metabolic abnormalities have all been implicated in the development and progression of diabetic cardiomyopathy. Molecular mechanisms linked to the underlying pathophysiological changes include abnormalities in AMP-activated protein kinase, peroxisome proliferator-activated receptors, O-linked N-acetylglucosamine, protein kinase C, microRNA, and exosome pathways. The aim of this review is to provide a contemporary view of these instigators of diabetic cardiomyopathy, as well as mechanistically based strategies for the prevention and treatment of diabetic cardiomyopathy. 10.1161/CIRCRESAHA.117.311586
    Exosomal Mst1 transfer from cardiac microvascular endothelial cells to cardiomyocytes deteriorates diabetic cardiomyopathy. Hu Jianqiang,Wang Shanjie,Xiong Zhenyu,Cheng Zheng,Yang Zhi,Lin Jie,Wang Tingting,Feng Xinyu,Gao Erhe,Wang Haichang,Sun Dongdong Biochimica et biophysica acta. Molecular basis of disease Diabetic cardiomyopathy (DCM) is characterized by cardiac microvascular endothelial cells (CMECs) injury and cardiomyocyte (CM) dysfunction. Exosomes mediated cellular communication between CMECs and CM has emerging roles in the pathogenesis of DCM, but the underlining mechanisms are unclear. Mammalian sterile 20-like kinase 1 (Mst1), a key component in Hippo pathway which participates in regulating organ size, apoptosis and autophagy, is involved in the development of DCM. We generated the endothelial-specific Mst1 transgenic mice (Tg-Mst1) and constructed diabetic model with streptozotocin (STZ). Interestingly, Tg-Mst1 mice suffered from worse cardiac function and aggravated insulin resistance compared with non-transgenic (NTg) diabetic mice. The content of Mst1 protein was increased, while Mst1 mRNA had no significant change in CM isolated from diabetic Tg-Mst1 mice. In vitro, CMECs-derived exosomes were taken up by CM and increased Mst1 protein content which inhibited autophagy, as well as enhanced apoptosis in high glucose (HG) cultured CM as evidenced by immunofluorescence and western blot analysis. In addition, Mst1 inhibited glucose uptake under diabetic condition by disrupting the glucose transporter type 4 (GLUT4) membrane translocation through decreasing the interaction between Daxx and GLUT4, as well as enhancing the association of Mst1 and Daxx. Our study exemplifies pleiotropic effects of Mst1-enriched exosomes released from CMECs on inhibiting autophagy, promoting apoptosis and suppressing the glucose metabolism in CM. 10.1016/j.bbadis.2018.08.026
    Targeting miRNA for Therapy of Juvenile and Adult Diabetic Cardiomyopathy. Nandi Shyam Sundar,Mishra Paras Kumar Advances in experimental medicine and biology Prevalence of diabetes mellitus (DM), a multifactorial disease often diagnosed with high blood glucose levels, is rapidly increasing in the world. Association of DM with multi-organ dysfunction including cardiomyopathy makes it a leading cause of morbidity and mortality. There are two major types of DM: type 1 DM (T1D) and type 2 DM (T2D). T1D is diagnosed by reduced levels of insulin and high levels of glucose in the blood. It is caused due to pancreatic beta cell destruction/loss, and mostly found in juveniles (juvenile DM). T2D is diagnosed by increased levels of insulin and glucose in the blood. It is caused due to insulin receptor dysfunction, and mostly found in the adults (adult DM). Both T1D and T2D impair cardiac muscle function, which is referred to as diabetic cardiomyopathy. We and others have reported that miRNAs, a novel class of tiny non-coding regulatory RNAs, are differentially expressed in the diabetic heart and they contribute to diabetic cardiomyopathy. Here, we elaborated the biogenesis of miRNA, how miRNA regulates a gene, cardioprotective roles of different miRNAs including miRNAs present in exosomes, underlying molecular mechanisms by which miRNA ameliorates diabetic cardiomyopathy, and the role of miRNA as a potential therapeutic target for juvenile and adult diabetic cardiomyopathy. 10.1007/978-3-319-74470-4_4
    The Exosome: a New Player in Diabetic Cardiomyopathy. Tao Lichan,Shi Jia,Yang Xiaoyu,Yang Ling,Hua Fei Journal of cardiovascular translational research Diabetic cardiomyopathy (DCM) or diabetes-induced cardiac dysfunction is a direct consequence of uncontrolled metabolic syndrome and occurs worldwide. However, the underlying cellular and molecular mechanisms remain poorly understood. Recently, exosomes have attracted considerable interest for their use as efficient, targeted, and non-immunogenic delivery systems for biological molecules or pharmacotherapies. This review will summarize the fast-developing field of the regulation and function of exosomes in DCM, affording valuable insights and therapeutic opportunities in combatting diabetes-related cardiac disorder for modern human health. 10.1007/s12265-018-9825-x
    Pathological Effects of Exosomes in Mediating Diabetic Cardiomyopathy. Salem Esam S B,Fan Guo-Chang Advances in experimental medicine and biology Diabetic subjects are at risk of developing cardiovascular disease, which accounts for 60-80% of diabetes-related mortality. Atherosclerosis is still considered as a leading cause of heart failure in diabetic patients, but it could also be an intrinsic and long-term effect of contractile cardiac cells malfunction, known as diabetic cardiomyopathy (DCM). Pathologically, this cardiac dysfunction is manifested by inflammation, apoptosis, fibrosis, hypertrophy and altered cardiomyocytes metabolism. However, the underlying molecular mechanisms of DCM pathophysiology are not clearly understood. Recent and several studies have suggested that exosomes are contributed to the regulation of cell-to-cell communication. Therefore, their in-depth investigation can interpret the complex pathophysiology of DCM. Structurally, exosomes are membrane-bounded vesicles (10-200 nm in diameter), which are actively released from all types of cells and detected in all biological fluids. They carry a wide array of bioactive molecules, including mRNAs, none-coding RNAs (e.g., microRNAs, lncRNAs, circRNAs, etc), proteins and lipids. Importantly, the abundance and nature of loaded molecules inside exosomes fluctuate with cell types and pathological conditions. This chapter summarizes currently available studies on the exosomes' role in the regulation of diabetic cardiomyopathy. Specifically, the advances on the pathological effects of exosomes in diabetic cardiomyopathy as well as the therapeutic potentials and perspectives are also discussed. 10.1007/978-981-10-4397-0_8