Abstract 12156: Small Proline-Rich Repeat Protein 1a is a Significant Functional Target of Microrna-150 in Mouse Hearts and Human Cardiac Fibroblasts

Abstract

Background and Aims: Cardiac injury induces dynamic changes in the expression of microRNAs (miRs). MiR-150 is conserved between rodents and humans, and its downregulation is markedly associated with heart failure (HF) severity and outcome in humans. Using systemic and cardiomyocyte (CM)-specific knockout (KO) mouse models, we reported that miR-150 plays a cardioprotective role in part by decreasing CM apoptosis, and that pro-apoptotic small proline-rich protein 1a ( Sprr1a ) is a direct and functional target of miR-150 in CMs. We also showed that Sprr1a knockdown in mice improves cardiac dysfunction and fibrosis post-myocardial infarction (MI), and that Sprr1a is upregulated in mouse cardiac fibroblasts (CFs) isolated from ischemic myocardium. However, the direct functional relationship between miR-150 and SPRR1A in MI and human CF (HCF) activation has never been established. Methods & Results: Here, we demonstrate using a novel miR-150 KO; Sprr1a -hypomorphic ( Sprr1a hypo/hypo ) mouse model that Sprr1a knockdown blunts cardiac dysfunction, damage, inflammation, apoptosis and fibrosis post-MI caused by miR-150 loss. MiR-150 KO; Sprr1a hypo/hypo mice also exhibit decreased pro-fibrotic markers in the infarct areas of hearts as compared to miR-150 KO mice. Our primary adult HCF studies further reveal that SPRR1A is upregulated in HCFs subjected to simulated ischemia/reperfusion, while its expression is downregulated in HCFs by a cardioprotective β-blocker carvedilol, which is inversely associated with miR-150 expression. MiR-150 knockdown in HCFs also increases pro-fibrotic SPRR1A . Lastly, protective roles of miR-150 in HCFs are in part mediated by the functional repression of SPRR1A (See Figure). Conclusions: Our findings delineate a pivotal functional interaction between miR-150 and Sprr1a as a novel regulatory mechanism pertinent to CF activation post-MI. This axis could be a therapeutic target for intervention in ischemic HF and cardiac fibrosis.