Abstract
MicroRNA-150 (miR-150) is downregulated in patients with multiple cardiovascular diseases and in diverse mouse models of heart failure (HF). miR-150 is significantly associated with HF severity and outcome in humans. We previously reported that miR-150 is activated by β-blocker carvedilol (Carv) and plays a protective role in the heart using a systemic miR-150 KO mouse model. However, mechanisms that regulate cell-specific miR-150 expression and function in HF are unknown. Here, we demonstrate that potentially novel conditional cardiomyocyte–specific (CM-specific) miR-150 KO (miR-150 cKO) in mice worsens maladaptive cardiac remodeling after myocardial infarction (MI). Genome-wide transcriptomic analysis in miR-150 cKO mouse hearts identifies small proline–rich protein 1a (Sprr1a) as a potentially novel target of miR-150. Our studies further reveal that Sprr1a expression is upregulated in CMs isolated from ischemic myocardium and subjected to simulated ischemia/reperfusion, while its expression is downregulated in hearts and CMs by Carv. We also show that left ventricular SPRR1A is upregulated in patients with HF and that Sprr1a knockdown in mice prevents maladaptive post-MI remodeling. Lastly, protective roles of CM miR-150 are, in part, attributed to the direct and functional repression of proapoptotic Sprr1a. Our findings suggest a crucial role for the miR-150/SPRR1A axis in regulating CM function post-MI.
Highlights
Modulation of microRNA activity in the heart is an important mechanism that underlies the pathogenesis of heart failure (HF) [1,2,3,4,5]
We show that the expression of small proline–rich protein 1a (Sprr1a) is upregulated in CMs isolated from ischemic myocardium but is downregulated in hearts and CMs by Carv; cardiac Small proline–rich protein 1a (SPRR1A) is upregulated in patients with HF with reduced ejection fraction (HFrEF), which is inversely associated with the expression of miR-150
We identified that miR-150 directly inhibits proapoptotic Sprr1a such that the increased expression of Sprr1a in CM-specific miR-150 cKO mice or that CMs lacking miR-150 result in a higher degree of sustained CM death during ischemic stress
Summary
Modulation of microRNA (miR) activity in the heart is an important mechanism that underlies the pathogenesis of heart failure (HF) [1,2,3,4,5]. Clinical trials using potentially novel miR therapies are underway for other diseases [6,7,8,9] and more recently for HF (e.g., NCT04045405; ClinicalTrials.gov). The circulating or cardiac miR–150-5p (hereafter referred to as miR-150) is downregulated in patients with multiple cardiovascular diseases (CVDs) such as acute myocardial infarction (AMI), atrial fibrillation, dilated cardiomyopathy (DCM), and ischemic cardiomyopathy [10,11,12,13], as well as in various mouse models of HF (MI, transverse aortic constriction [TAC], and ischemia/reperfusion [I/R] injury) [14,15,16]. Previous data from both human and rodent studies establish the strong clinical relevance, as well as potential diagnostic, prognostic, and therapeutic applications of miR-150. The extent to which expression of miR-150 selectively in CMs regulates MI is unknown, and there is a lack of mechanistic insight by which CM miR-150 modulates cardiac protection
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