MicroRNA-27a Regulates Beta Cardiac Myosin Heavy Chain Gene Expression by Targeting Thyroid Hormone Receptor β1 in Neonatal Rat Ventricular Myocytes

Abstract

MicroRNAs (miRNAs), small noncoding RNAs, are negative regulators of gene expression and play important roles in gene regulation in the heart. To examine the role of miRNAs in the expression of the two isoforms of the cardiac myosin heavy chain (MHC) gene, ␣-and ␤-MHC, which regulate cardiac contractility, endogenous miRNAs were downregulated in neonatal rat ventricular myocytes (NRVMs) using lentivirus-mediated small interfering RNA (siRNA) against Dicer, an essential enzyme for miRNA biosynthesis, and MHC expression levels were examined. As a result, Dicer siRNA could downregulate endogenous miRNAs simultaneously and the ␤-MHC gene but not ␣-MHC, which implied that specific miRNAs could upregulate the ␤-MHC gene. Among 19 selected miRNAs, miR-27a was found to most strongly upregulate the ␤-MHC gene but not ␣-MHC. Moreover, ␤-MHC protein was downregulated by silencing of endogenous miR-27a. Through a bioinformatics screening using TargetScan, we identified thyroid hormone receptor ␤1 (TR␤1), which negatively regulates ␤-MHC transcription, as a target of miR-27a. Moreover, miR-27a was demonstrated to modulate ␤-MHC gene regulation via thyroid hormone signaling and to be upregulated during the differentiation of mouse embryonic stem (ES) cells or in hypertrophic hearts in association with ␤-MHC gene upregulation. These findings suggested that miR-27a regulates ␤-MHC gene expression by targeting TR␤1 in cardiomyocytes.

The microRNA-27a: ZBTB10-specificity protein pathway is involved in follicle stimulating hormone-induced VEGF, Cox2 and survivin expression in ovarian epithelial cancer cells

“…In addition, microRNA-27a was demonstrated to modulate the cardiac β-myosin heavy chain gene via thyroid hormone signaling (14). Li et al confirmed that antisense microRNA-27a and overexpression of ZBTB10 blocked estrogen-induced transactivation in breast cancer (15).…”

In Vivo Differentiation of Induced Pluripotent Stem Cell-Derived Cardiomyocytes

“…However, transplanting iPSC-CMs into the heart induced a transition from the β to the α MHC isoform, a transition seen during cardiac development and maturation. 35 Although this study did not investigate changes in mitochondrial quantity or structure in iPSC-CMs after transplantation into the heart, the maturing of MHC after transplantation implies a functional imjunctions with the basement membrane, possibly enhancing the integration of transplanted iPSC-CMs into the heart.…”

microRNA expression profiling in fetal single ventricle malformation identified by deep sequencing

“…The absence of miR-133a expression results in ectopic expression of smooth muscle genes in the heart and aberrant cardiomyocyte proliferation (8). Targeted deletion of miR-126 displays defective cardiac neovascularization in mice that survive myocardial infarction (14); miR-206 is involved in apoptotic cell death in myocardial infarction by post-transcriptional repression of IGF-1 (15); and miR-27a regulation of β-MHC gene expression by targeting TRβ1 has been identified in cardiomyocytes (16). Other differentially expressed miRNAs between SV and control cardiac tissues were not investigated and further research is required to evaluate their roles in cardiac development.…”