Abstract Body: Cardiovascular disease remains the leading cause of death worldwide, and heart failure following myocardial infarction (MI), which continues to carry a poor prognosis underscoring the need for novel mechanistic insights and innovative therapeutic approaches. Small nucleolar RNAs (snoRNAs), traditionally recognized for their roles in RNA modifications and processing. However, their functional contribution to acute cardiac injury and post-ischemic repair is largely unexplored.
We investigated a MI-small-Cajal body like RNA (MI-scarna) as a novel regulator of post-MI remodeling. MI-scarna expression was significantly downregulated post-MI in mouse hearts, and cardiac endothelial cells isolated from MI-hearts. In vitro knockdown of MI-scarna markedly impaired angiogenic capacity and significantly increased mouse cardiac endothelial cell death under basal conditions. Whereas MI-scarna overexpression (OE) in vitro enhanced angiogenic activity and protected against to hypoxia-induced cell death. Endothelial cell-specific OE of MI-scarna attenuated ischemia/reperfusion injury ex vivo and significantly improved left ventricular function following MI in mice. Mechanistically, MI-scarna modulated U4-snRNA methylation and regulated Wilms Tumor-1 expression, thereby promoting reparative signaling pathways after ischemic injury. Collectively, these findings identify MI-scarna as a previously unrecognized regulator of post-ischemic cardiac repair and suggest its potential as a therapeutic target to mitigate adverse cardiac remodeling in adult cardiovascular disease.