Abstract 14979: MicroRNA-342-3p Regulates Post-Ischemic Angiogenesis in Diabetic Mice

Abstract

Introduction: Diabetic patients are more likely to suffer from adverse cardiovascular events such as myocardial infarction (MI) compared to non-diabetics. Angiogenesis is crucial to limiting infarct size. However, this angiogenic response is blunted in patients with diabetes. MicroRNAs (miRNAs) have been shown to affect both physiological and pathological angiogenesis. However, the role of miRNAs in MI-associated angiogenesis in diabetes remains poorly defined. Here, we describe a novel role of miRNA-342-3p in angiogenesis following ischemic injury to the myocardium. Methods: We performed RNA sequencing on cardiac endothelial cells of Ldlr-deficient mice on either chow or high fat sucrose containing (HFSC) diet at 0-, 3-, 7- and 14-days post-MI. Gain and loss of function studies, functional assays, RNA-seq, bioinformatics, RNA-FISH, and light-sheet microscopy were used to ascertain the function and mechanism of this miRNA. Results: miR-342-3p was upregulated in cardiac ECs during the vascular remodeling phase post-MI in chow-fed mice compared to the HFSC-fed group. Overexpression of miR-342-3p promotes the number of endothelial sprouts (140% vs control), cumulative sprout length (311% vs control) and scratch closure (AUC 83% vs control, p <0.0001) in endothelial cells (ECs), whereas its inhibition had anti-angiogenic effects. Capillary density and EC proliferation (ki67 + /CD31 + ) increased by 107% and154% respectively in the border zone of hearts injected with miR-342-3p mimics compared to control in HFSC diet fed Ldlr -/- mice 7 days after permanent LAD ligation. Using a combination of RNA-seq and prediction algorithms, Decorin (DCN), a small Leucine rich protein with anti-angiogenic properties, was identified as a target of miR-342-3p. Western blot analysis confirmed significant knockdown of Decorin protein by 94% in HUVECs transfected with miR-342-3p mimics compared to controls. RNA seq profiling of overexpressing ECs implicated the ID1 signaling pathway. Conclusion: These results identify a novel role for miR-342-3p in the regulation of angiogenesis post-MI in diabetes. miR-342-3p overexpression rescues impaired angiogenesis in diabetic hearts via the suppression of Decorin, providing new targets for therapeutic angiogenesis.