Abstract 18076: MicroRNA-342-3p Rescues Post-Ischemic Cardiac Function in Diabetic Mice via HGF-MET Pathway Activation

Abstract

Introduction: - Patients with diabetes have a poorer prognosis following myocardial infarction compared to healthy controls. This is partly due to impaired post-ischemic angiogenesis in the diabetic heart. The role of microRNAs (miRs) in angiogenesis is relatively unexplored. miR expression is responsive to stimuli such as hypoxia, metabolic environment, growth factors, etc. Here, we describe how miR-342-3p, a hypoxia-responsive miR, regulates angiogenesis under physiologic and diabetic conditions. Methods: - miR-342-3p or control mimic was injected into the border zone of hearts post-ischemia/reperfusion in male Ldlr -/- mice on a high fat and high sucrose (HFSC) diet. Echocardiography, histology, immunofluorescence, RNA FISH and in vitro assays were used to elucidate the mechanism of action of this miR. Results: - Ejection fraction (EF) and fractional shortening (FS) of miR-342-3p injected hearts were significantly higher by 145% and 173%, respectively, at day 14 compared to controls (p = 0.0204 and p = 0.0095). Capillary density as well as ki67+ endothelial cells were more abundant by 107% and 154%, respectively (p = 0.0371 and p = 0.0242) vs control. RNA sequencing of miR-342-3p overexpressing endothelial cells implicated HGF-MET signaling as one of the top upregulated pathways. Western blots (WB) revealed an increase in MET expression (p = 0.0255) in miR-342-3p overexpressing cells vs control. Decorin (DCN) was identified as a direct target of miR-342-3p and validated by WB and luciferase reporter assays. Hypoxia (2% O 2 ) induced miR-342-3p expression (p = 0.0023) while suppressing DCN levels. However, both high glucose (25 mM) and palmitate (100 μM) treatments blunted the miR-342-3p induction while increasing Decorin levels. Co-IP and microscopy were used to show Decorin-MET co-localization. Lastly, miR-342-3p and DCN were inversely expressed (p = 0.0188 and p = 0.0015 respectively) in diabetic and healthy ECs obtained from patients. Conclusion: - These findings establish a critical role for miR-342-3p in regulating cardiac angiogenesis post-ischemic injury in diabetic mice. Under diabetic conditions, the hypoxia induced expression of miR-342-3p is blunted, leading to Decorin mediated degradation of MET receptors, which impairs angiogenesis.