Small Extracellular Vesicle External Surface Adiponectin-Mediated Adipocytes/Cardiomyocytes Communication in Diabetic Ischemic Heart Failure

BACKGROUND: Mortality from acute myocardial infarction (MI) has declined significantly in the past decade for nondiabetic patients. However, both morbidity and mobility of ischemic heart failure (IHF) persistently escalate in the diabetic population via incompletely understood mechanisms. Recent studies demonstrated that small extracellular vesicles (sEVs) released from nondiabetic and diabetic adipocytes (ADps) exert opposite effects on acute myocardial ischemia and reperfusion (MI/R) injury. However, whether and how ADp sEVs may protect against post-MI remodeling and IHF, and more important, whether and how diabetes may impair this protective effect, remain unknown. METHODS: sEVs were isolated from epididymal fat pads of nondiabetic animals and intramyocardially injected in nondiabetic or diabetic hearts subjected to MI (90 minutes of MI per 4 weeks of reperfusion). RESULTS: sEV treatment significantly attenuated post-MI cardiac remodeling and improved cardiac function in nondiabetic mice. However, the protection was not observed in diabetic hearts. In adult cardiomyocytes isolated from nondiabetic hearts, sEVs rapidly (15 minutes) activated cell salvage kinases (ERK extracellular signal-regulated kinase, AMPK AMP-activated protein kinase, and ACC acetyl-CoA carboxylase) and suppressed oxidative stress-induced cell death, suggesting sEV external surface molecules are responsible for the observed cytoprotection. The Exo-Flow (a technology detecting sEV external surface molecules) demonstrated that adiponectin (APN) is enriched on the sEV external surface. The sEVs from APN knockout mice or APN neutralization (NU) antibody pretreated sEVs failed to protect the heart against IHF. Moreover, the cardioprotective effects of sEVs were abolished in APN receptor-1 (AdipoR1)-deficient mice (the primary receptor for APN signaling in the heart) or in mice overexpressing GRK2 (G-protein-coupled receptor kinase 2, a kinase that phosphorylates and inactivates AdipoR1). Finally, diabetes significantly increased cardiac GRK2 expression and AdipoR1 phosphorylation, which prevented sEVs from exerting their beneficial effects. Restoring AdipoR1 function by knockin a mutated phosphorylation-resistant AdipoR1 (AdipoR1S205A) via AAV9 (adeno-associated virus 9)-mediated gene delivery rescued ADp sEV cardioprotection in diabetic mice. CONCLUSIONS: Our study reveals that APN is enriched on the ADp-derived external surface of sEVs and is biologically active, playing a critical role in ADp-cardiomyocyte communication. Diabetes disrupts this communication by enhancing GRK2-mediated AdipoR1 phosphorylation, impairing sEV signaling, and exacerbating IHF. These findings provide new insights into the pathophysiology and therapy of IHF in diabetes.