Exosomes in Diabetic Cardiomyopathy: The Next-Generation Therapeutic Targets?

Abstract

The uncontrolled rapid growth of diabetes represents a global burden. Subjects with diabetes are at increased risk of cardiovascular disease, including a higher case fatality rate in myocardial infarction or stroke. However, the underlying pathogenesis and distinct mechanisms of diabetic cardiovascular complications are not clearly understood, thus limiting the development of novel preventive and treatment strategies. Cardiac cell communication via extracellular vesicles in healthy and pathological conditions is an emerging area of research. Exosomes are endogenous nanovesicles (30–100 nm circa), which are actively secreted out of cells of different types and are present in all studied biological fluids. Exosomes carry a composite cargo of molecules, including microRNAs, proteins, and lipids. Interestingly, it is emerging that the quality and quantity of molecules in such cargo vary with cell types and the environmental conditions. Moreover, the exosome cargo is at least in part transferrable to other cell types, with variable capacities for receiving such exosomes. Recipient cells respond to exosome uptake with expressional and functional changes. The study by Wang et al. (1) advances our understanding of the role of cardiomyocyte exosomes and hints at the complexity of exosomal cargo under diabetic conditions. One of the novel findings from the study demonstrates that heat shock protein (Hsp) 20, a chaperone protein from the HSP family that plays an important role in cellular intrinsic defense mechanisms, may enhance production of exosomes in cardiomyocytes via directly interacting with Tsg101, an upstream endosomal membrane transport protein involved in the exosome biogenesis pathway. Further, the authors used GW4869, an inhibitor of neutral sphingomyelinase/ceramide, to block the release of exosomes from cardiac cells in vivo, which ameliorated cardiac function in wild-type mice with streptozotocin-mediated induction of type 1 diabetes. This observation suggests that pathogenic exosomes carrying and diffusing detrimental signals contribute to the development of diabetic cardiomyopathy. …