Cardiomyocyte microRNA-150 confers cardiac protection and directly represses proapoptotic small proline–rich protein 1A

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.

MiR-150 blunts cardiac dysfunction in mice with cardiomyocyte loss of β1-adrenergic receptor/β-arrestin signaling and controls a unique transcriptome

“…Since miR-150 negatively regulates CM apoptosis in vitro and in vivo [ 25 , 26 ], we next examined whether the novel upstream regulator of miR-150, Gm41664 regulates CM apoptosis. We first find that Gm41664 knockdown in CMs decreases apoptotic p53 , Casp14 , and Ing-4 while miR-150 knockdown increases the expression of these apoptotic genes (Fig.…”

“…We showed using a miR-150 KO mouse model that miR-150 is protective in MI by decreasing CM apoptosis [ 25 ]. We also demonstrated that CM-specific miR-150 cKO mice worsen apoptosis and adverse remodeling post-MI [ 26 ]. Another group reported that miR-150 overexpression protects the heart from acute MI by suppressing the monocyte migration [ 31 ].…”

“…Using a miR-150 knockout (KO) mouse model, we reported that β 1 AR/β-arrestin-responsive miR-150 is protective in myocardial infarction (MI) in part via suppressing CM apoptosis [ 25 ]. More recently, we demonstrated that CM-specific miR-150 conditional KO (cKO) mice augment apoptosis and maladaptive post-MI remodeling partially by inducing apoptotic genes in CMs [ 26 ]. Interestingly, miR-150 is downregulated in patients with many cardiovascular diseases (CVDs) [ 27 – 30 ] and diverse rodent models of HF [ 25 , 31 , 32 ].…”

Non-coding RNAs: Important participants in cardiac fibrosis

“…Low circulating levels of miR-150 were associated with LV remodeling after first ST-elevation acute MI ( 46 ). During acute MI, expression of miR-150 was remarkably decreased; restoration of its expression could improve cardiac function, reduce infarct areas, and attenuate fibrosis ( 47 – 50 ). Mechanically, miR-150 could reduce monocyte accumulation to myocardium by inhibiting CXCR4, decrease CMs apoptosis through repressing pro-apoptotic genes small proline–rich protein 1a (SPRR1a), egr2 and p2×7r, and prevent activation of CFs via downregulating pro-fibrotic Homeobox a4 (Hoxa4) ( 47 – 50 ).…”

Exosomal miR‑152‑5p/ARHGAP6/ROCK axis regulates apoptosis and fibrosis in cardiomyocytes

“…MicroRNAs (miRNAs, miRs) from plasma exosomes have been reported to be ideal biomarkers for the early identification of cardiovascular disease and to have great potential for therapeutic and other applications (11,12). There is evidence to suggest that a series of important physiological processes, including the survival, proliferation and angiogenesis of cardiomyocytes are regulated by miRNAs (13,14). In addition, miRNAs have been shown to stimulate cardiomyocyte proliferation and promote cardiac repair (15,16).…”