Abstract 531: Urolithin a Suppress Cardiac Fibrosis via Autophagy Pathway in the Diabetic Cardiomyopathy

Abstract

Objective: The cardiovascular protective effect of Urolithins remains poorly understood, despite wide-spread human exposure via the dietary consumption of their metabolic precursors, the ellagitannins, which is found in the pomegranate fruit. We identified Urolithin A (UA) as a natural compound that induces mitophagy and protects against diabetic cardiomyopathy both in vivo and in vitro. Healthy male C57BL/6 mice were fed with a High-fat diet for 6 months combined with a small dose of STZ injection to establish the T2DM model. Compared with the control, the diabetic mice suffered from cardiac dysfunction characterized by decrease EF, FS and E/A ratio, which was reversed with UA treatment. Masson staining and collagen marker Immunoblots showed that cardiac fibrosis was also decreased with UA treatment in the diabetic mice both in vivo and in vitro. Interestingly, we found UA significantly activated mitophagy and increased the co-localization of Myto-tracker and Lysotracker. However, we found UA increased Drp1 expression but not PINK1 or Parkin phosphorylation indicating a non-canonical mitophagy pathway. We treated the cardiac fibroblast with Drp1 siRNA and found the protective effect of UA against cardiac fibrosis was abolished. Conclusion: UA protected against diabetic cardiomyopathy by activating mitophagy vias a non-canonical pathway. Keywords: Diabetic cardiomyopathy; Cardiac fibrosis; Urolithin A; Autophagy; Mitophagy