Mechanisms of cardioprotective Y RNA signaling in macrophages

PROJECT SUMMARY/ASTRACT Myocardial infarction (MI) is an acute event that precipitates chronic cardiovascular disease. As such, therapeutics that reduce infarct size have the potential to stem the tide of downstream cardiovascular diseases including heart failure. To date, current strategies either alleviate symptoms or, at best, slow the progress of disease progression. A major untapped potential lies in the vast and poorly understood world of small non-coding RNA. A promising catalog for prospecting potentially therapeutic small RNAs is in the secretome of cells with demonstrated tissue-reparative capacity. IMEX are EVs secreted by therapeutically-enhanced cardiac stromal cells. One small non-coding RNA enriched in IMEX derives from the YRNA 4 gene and dubbed yREX3. Previous work demonstrate that yREX3 triggers profound transcriptomic effects in monocyte-derived macrophages compared to other cell types in the heart. Specifically, yREX3 methylates Pick1 expression and enhances their ability to clear dead cells, a process called efferocytosis. In this proposal, we propose to dissect the mechanism of yREX3 signaling macrophages to enhance efferocytosis and cardioprotection. In Aim 1, we will confirm the signaling events by yREX3 in macrophages to enhance efferocytosis. In Aim 2, we will investigate the direct contribution of macrophages on tissue healing. Finally, in Aim 3, we will investigate the indirect effects of yREX3- primed macrophages in cardioprotection. Understanding the mechanism of action of therapeutic small RNAs (in their target cells) would represent a significant step toward both mechanistic understanding and advance toward curative treatment for MI.