miR-199b-5p is a regulator of left ventricular remodeling following myocardial infarction

摘要

Myocardial infarction (MI), the globally leading cause of heart failure, morbidity and mortality, involves post-MI ventricular remodeling, a complex process including acute injury healing, scar formation and global changes in the surviving myocardium. The molecular mechanisms involved in adverse post-infarct left ventricular remodeling still remain poorly defined. Recently, microRNAs have been implicated in the development and progression of various cardiac diseases as crucial regulators of gene expression. We previously demonstrated that in a murine model of pressure overload, a model of heart failure secondary to aortic stenosis or chronic high blood pressure, elevated myocardial expression of miR-199b-5p is sufficient to activate calcineurin/NFAT signaling, leading to exaggerated cardiac pathological remodeling and dysfunction. Given the differences in left ventricular remodeling secondary to post-infarct healing and pressure overload, we evaluated miR-199b function in post-MI remodeling. We confirmed that the expression of miR-199b is elevated in the post-infarcted heart. Transgenic animals with cardiomyocyte-restricted overexpression of miR-199b-5p displayed exaggerated pathological remodeling after MI, reflected by severe systolic and diastolic dysfunction and fibrosis deposition. Conversely, therapeutic silencing of miR-199b-5p in MI-induced cardiac remodeling by using an antagomir to specifically inhibit endogenous miR-199b-5p in?vivo , resulted in efficient suppression of cardiac miR-199b-5p expression and attenuated cardiac dysfunction and dilation following MI. Mechanistically, miR-199b-5p influenced the expression of three predicted target genes in post-infarcted hearts, dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1a), the notch1 receptor and its ligand jagged1. In conclusion, here we provide evidence supporting that stress-induced miR-199b-5p participates in post-infarct remodeling by simultaneous regulation of distinct target genes. prs.rt("abs_end"); 1. Introduction Acute myocardial infarction (MI) is one of the major causes of mortality and morbidity in humans [1] . MI occurs when blood supply to the left ventricular (LV) wall of the heart is hindered due to an occlusion in the coronary arteries [2] and consequently leading to massive cardiomyocyte death. A complex remodeling process is then initiated involving scar formation in the infarct zone, interstitial fibrosis in the border zone between the infarct and non-infarct area, cardiomyocyte hypertrophy and capillary rarefaction in the non-infarct remote zone. Eventually, these changes provoke impaired cardiac contractility and, ultimately, heart failure [3] . Moreover, post-infarction remodeling is associated with a higher incidence of arrhythmia and sudden cardiac death [4] . Hence, therapeutic strategies targeting pathological remodeling following MI could provide a promising strategy for post-MI management and heart failure. In this regard, we and others have identified a variety of stress-induced microRNAs (miRNAs) as regulators of crucial mechanisms in the development of heart failure and acting as promising therapeutic targets [5] ; [6] ; [7] ; [8] ; [9] ; [10] . These short (～22 nucleotide) single stranded RNA molecules modulate gene expression by binding to ‘seed regions’ on protein-coding transcripts and leading to translational inhibition or degradation of mRNAs [11] . Importantly, a single miRNA likely simultaneously targets dozens of mRNAs, while individual mRNAs display several seed regions for different miRNAs, providing and enormous regulatory capacity for post-transcriptional gene regulation. Previously, stress-induced miR-199b-5p was identified as a potent regulator of pathologic cardiac hypertrophy by functioning as an activator of calcineurinuclear factor of activated T-cell (CnA/NFAT) signaling [5] . miR-199b-5p exerts its function by targeting Dual-specificity tyrosine-phosphorylation regulated kinase 1a ( Dyrk1a ), a nuclear kinase responsible for NFAT rephosphorylation and translocation from the nucleus to the cytoplasm, essentially acting as an inhibitor of CnA/NFAT signaling. Therapeutic inhibition of miR-199b-5p by using a cholesterol-conjugated antagomir provoked inhibition of cardiac CnA/NFAT activity, attenuated pathological remodeling and preserved cardiac contractility after pressure overload, identifying miR-199b-5p as a therapeutic target to treat hypertension-induced forms of heart failure [5] . In the present study, we aimed at exploring the function of miR-199b-5p (referred to as miR-199b), if any, in post-infarct remodeling in the mouse using gain-of-function and therapeutic silencing approaches. We confirmed that the expression of miR-199b is elevated in the post-infarcted heart. Transgenic animals with cardiomyocyte-restricted overexpression of miR-199b displayed exaggerated pathological remodeling after MI, reflected by severe systolic and diastolic dysfunction and fibrosis d