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

Abstract

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.

Construction and Investigation of a circRNA-Associated ceRNA Regulatory Network in Tetralogy of Fallot

“…Among the module, miR-199b-5p serves as a bridge between the circRNA and the mRNA. Coincidentally, miR-199b-5p was identi ed to participate in left ventricular remodeling, associated with pathologic cardiac hypertrophy [35][36][37]. These studies are in accordance with our nding showing hsa_circ_0007798/miR-199b-5p/HIF1A regulatory module is associated with the cardiac defects, including the TOF.…”

Circulating miRNAs as Potential Biomarkers Associated with Cardiac Remodeling and Fibrosis in Chagas Disease Cardiomyopathy

“…Calcineurin/NFAT signaling is apparently regulated by the expression levels of miR-199b-5p in cardiac remodeling and dysfunction [23]. In our study, circulating miR-199b-5p levels were not increased in Chagas disease patients, when compared to healthy controls.…”

“…Altered expression levels of circulating microRNAs in different body fluids have been reported in several disease settings [13,14,15], including cardiovascular diseases [16,17]. In this context, studies demonstrated that miR-19a contributes to heart failure [18] whereas miR-21 [19], miR-29 [20,21], and the miR-30 family [22] contribute to cardiac fibrosis or hypertrophy, while miR-199b acts as a regulator of left ventricular remodeling, associated with cardiac hypertrophy [23].…”

Fibrosis in Chronic Kidney Disease: Pathogenesis and Consequences

“…Some miRs are regulated by the TGF-ß1 “core signaling pathway”, acting as downstream factors mediating a different pro-fibrotic action, which contributes to the excessive deposition of collagen and tissue fibrosis and they can also facilitate the process of EMT [ 90 , 91 , 92 , 93 , 94 ]. There is a large list of miRs whose overexpression has shown to be able to induce renal and cardiac fibrosis: miR-21 [ 91 , 95 , 96 , 97 ], miR-34 [ 98 , 99 , 100 ] miR-132 [ 101 , 102 ], miR-192 [ 103 ], miR-199 [ 104 , 105 ], miR-214 [ 106 ], and miR-433 [ 107 ]; meanwhile, their downregulation has shown to decrease renal and cardiac fibrosis.…”