Abstract 12304: Activation of the Exosome Biogenesis Pathway in Cardiomyocytes by Overexpression of Hsp20 Improves Cardiac Function and Angiogenesis in Diabetic Mice

Abstract

Background: Exosomes derived from cardiomycytes are able to affect endothelial cell growth. Increased Hsp20 levels in myocytes have been shown to promote cardiac angiogenesis. Given that diabetic hearts exhibit severe microvascular rarefaction and impaired angiogenesis, we asked whether overexpression of Hsp20 could attenuate diabetes-triggered cardiac adverse remodeling, and if so, whether Hsp20-mediated cardioprotection is associated with the activation of exosome biogenesis/release. Methods and Results: 2-mon old male wild-type (WT) mice and transgenic (TG) mice with heart-specific overexpression of Hsp20 (10-fold) underwent daily peritoneal injection of streptozotocin (STZ, 50μg/g) for 5 days to induce diabetic condition (>300mg/dl). Control mice were received injections of citrate buffer. 3-month later, we observed that the left ventricular ejection fraction (EF) and fractional shortening (FS) were reduced by 43% and 35%, respectively, in STZ-injected WT mice, compare to controls. However, STZ-induced cardiac dysfunction was significantly attenuated in Hsp20-TG mice, compared to WTs. The wheat germ agglutinin (WGA) staining displayed that the size of cardiomyocytes was significantly increased in STZ-WT hearts, but not in STZ-Hsp20TG samples, compared to controls. Similarly, STZ could greatly induce myocardial fibrosis and apoptosis in WT hearts, but not significant in Hsp20-TGs. In addition, the density of myocardial blood vessels, measured by Isolectin IB4 staining, was decreased to a greater degree in STZ-WTs than STZ-TGs. Mechanistically, we observed that Hsp20 interacted with Tsg101, an initiator of exosome biogenesis in cells. As a result, the levels of Tsg101, Rab11a/b and Rab35, factors known to participate in exosome biogenesis/release, were significantly increased in Hsp20TG hearts, compared to WTs. Accordingly, blockade of exosome generation with GW4869 (2.5μg/g), a specific inhibitor of exosome biogenesis, offset cardio-protective effects observed in STZ-treated Hsp20-TG mice. Conclusions: This study indicates that overexpression of Hsp20 protects mouse hearts against diabetes-induced cardiac adverse remodeling via activation of exosome biogenesis/release in cardiomyocytes, at least in part.