Deciphering the novel regulatory mechanisms of neovascularization, cardiomyocyte survival, and endothelial cell-cardiomyocyte crosstalk in myocardial infarction

Myocardial infarction (MI) causes 1 of every 7 deaths in the United States. Because the heart has little regen- erative capacity after injury, an urgent need exists for novel strategies in MI therapy. MicroRNAs (miRs) are small noncoding RNAs that downregulate targets, and miRs are being pursued as novel therapies for heart failure in clinical trials. Vascularization is crucial for cardiomyocyte (CM) survival after MI. Ischemic insult re- sulting from insufficient blood supply to the heart results in reduced myocardial capillary flow reserve and capil- lary density, impaired tissue perfusion, and augmented cellular injury and scar formation, leading to progres- sive left ventricular remodeling and chronic heart failure. Because CM renewal is absent in adult mammalian hearts, dead CMs after MI are also replaced by scar tissue. Although the significance of endothelial dysfunc- tion and CM dropout in MI has been established, identification of the effectors underlying endothelial cell (EC) injury, CM dysfunction, and EC–CM crosstalk remains incomplete. Our goal here is to elucidate the roles of the novel EC- and CM-specific axis in MI. Beta-arrestin-mediated beta2-adrenergic receptor signaling (beta2AR/beta-arr signaling) elicited myocardial protection and in part contributed to the beneficial effects of the nonselective beta-blocker carvedilol. We discovered that carvedilol, acting through this mechanism, pro- moted the maturation of endothelial-enriched miR-532-5p (miR-532). Circulating miR-532 is a potential bi- omarker for MI. A secreted serine protease called PRSS23 initiates endothelial-to-mesenchymal transition and is essential for the cardiac valve formation in zebrafish embryo. Using innovative mouse models, we have made key discoveries: (1) systemic loss of Prss23, a key effector of miR-532, almost completely protects from cardiac dysfunction post-MI; and (2) systemic, EC-expressed, or CM-expressed miR-532 contributes to beneficial remodeling in ischemic hearts, which is opposed by EC-derived or CM-derived Prss23. Thus, dis- secting the pleiotropic mechanisms of action of the miR-532/PRSS23 axis may lead to the development of novel effective therapies for MI. Our hypothesis is that miR-532 elicits autocrine and paracrine protective ef- fects on ECs and CMs against ischemic stress by inhibiting maladaptive PRSS23 and cell extrinsic signals. To test our hypothesis, we plan to pursue three aims: (1) test if PRSS23 is a critical target of endothelial miR-532 and if pharmacological inhibition of PRSS23 promotes neovascularization post-MI; (2) determine the functional requirement of the CM-derived miR-532/PRSS23 axis during both murine post-MI remodeling and human CM damage; and (3) elucidate the key paracrine mechanisms by which the miR-532/PRSS23 axis in ECs regu- lates CM survival after ischemia. This proposal is innovative because the proposed functional axis has never been studied in a cell-type specific manner or with genetically modified mice. This project also employs trans- lational human cell and pharmacological studies and is significant because the identified beta2AR/beta- arr/miR-532-mediated PRSS23 regulatory mechanisms can be exploited as a novel target for MI. Project Number: 1R01HL180692-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Il-man Kim | Institution: INDIANA UNIVERSITY INDIANAPOLIS, INDIANAPOLIS, IN | Award Amount: $637,126 | Activity Code: R01 | Study Section: Therapeutic Development and Preclinical Studies Study Section[TDPS] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL18069201