LncRNA SNHG15 promotes angiogenesis and improves cardiac repair after myocardial infarction through MiR-665-mediated KDR expression.

Angiogenesis is crucial for prolonging survival of the injured myocardium following myocardial infarction (MI). Long non-coding RNAs (lncRNAs), recognized as a novel class of regulatory RNAs, play significant roles in various biological processes. However, their role in cardiac angiogenesis is not well elucidated. This study aimed to identify angiogenic lncRNAs and investigate their roles and mechanisms following MI. In our study utilizing lncRNA sequencing within a mouse model of MI, systematic lncRNA profiling identified differentially expressed transcripts in the MI border zone at 7 days post-MI, with SNHG15 being notably upregulated in cardiac tissue and endothelial cells (ECs) of the peri-infarct area. Overexpression of SNHG15 in human coronary artery endothelial cells (HCAECs) led to an increase in kinase insert domain receptor (KDR) expression and enhanced angiogenic activity. Furthermore, adeno-associated virus 9 (AAV9)-mediated overexpression of SNHG15, under the control of an endothelial-specific promoter, resulted in improved cardiac function, reduced infarct size, and increased angiogenesis in the infarcted myocardium in vivo. However, after endothelial-specific knockdown of SNHG15, cardiac function in mice with MI deteriorated. Localization studies revealed that SNHG15 is primarily found in the cytoplasm of HCAECs and mechanistic investigations indicated that SNHG15 acts as a competing endogenous RNA for miR-665, thereby regulating KDR signaling and expression. And KDR overexpression rescues both MI exacerbation and EC dysfunction induced by SNHG15 silencing in MI hearts. Collectively, our study has uncovered lncRNA SNHG15 as a novel regulator of angiogenesis that enhances the endogenous repair mechanisms of ECs in response to pathophysiological remodeling post-MI. These findings position SNHG15 as a promising therapeutic target for inhibiting infarct expansion and promoting cardiac repair and regeneration following MI.