Cardiomyocyte overexpression of miR-27b induces cardiac hypertrophy and dysfunction in mice

Abstract

Recent studies have begun to reveal critical roles of microRNAs (miRNAs) in the pathogenesis of cardiac hypertrophy and dysfunction. In this study, we tested whether a transforming growth factor-β (TGF-β)-regulated miRNA played a pivotal role in the development of cardiac hypertrophy and heart failure (HF). We observed that miR-27b was upregulated in hearts of cardiomyocyte-specific Smad4 knockout mice, which developed cardiac hypertrophy. In vitro experiments showed that the miR-27b expression could be inhibited by TGF-β1 and that its overexpression promoted hypertrophic cell growth, while the miR-27b suppression led to inhibition of the hypertrophic cell growth caused by phenylephrine (PE) treatment. Furthermore, the analysis of transgenic mice with cardiomyocyte-specific overexpression of miR-27b revealed that miR-27b overexpression was sufficient to induce cardiac hypertrophy and dysfunction. We validated the peroxisome proliferator-activated receptor-γ (PPAR-γ) as a direct target of miR-27b in cardiomyocyte. Consistently, the miR-27b transgenic mice displayed significantly lower levels of PPAR-γ than the control mice. Furthermore, in vivo silencing of miR-27b using a specific antagomir in a pressure-overload-induced mouse model of HF increased cardiac PPAR-γ expression, attenuated cardiac hypertrophy and dysfunction. The results of our study demonstrate that TGF-β1-regulated miR-27b is involved in the regulation of cardiac hypertrophy, and validate miR-27b as an efficient therapeutic target for cardiac diseases.

Epitranscriptional orchestration of genetic reprogramming is an emergent property of stress-regulated cardiac microRNAs

“…In this and other studies (32), miR-1 is down-regulated in early hypertrophy, consistent with a need to derepress its mRNA targets (histone deacetylase 4, heatshock proteins, insulin-like growth factor 1) during cardiac remodeling. Another homeostatic microRNA is the adipogenic inhibitor miR-27b, which targets the metabolic factors PPAR-γ and C/EBPα (33,34) and lipin-1 (current study). Our data show this to be the most-abundant up-regulated microRNA, consistent with metabolic remodeling induced by hypertrophy (16); its forced expression is sufficient to provoke pathological hypertrophy (34).…”

“…Another homeostatic microRNA is the adipogenic inhibitor miR-27b, which targets the metabolic factors PPAR-γ and C/EBPα (33,34) and lipin-1 (current study). Our data show this to be the most-abundant up-regulated microRNA, consistent with metabolic remodeling induced by hypertrophy (16); its forced expression is sufficient to provoke pathological hypertrophy (34).…”

Inhibitory effect of microRNA-27b on interleukin 17 (IL-17)-induced monocyte chemoattractant protein-1 (MCP1) expression

“…Sequence analysis revealed two binding sites in miR-27b and the MCP1 3'-UTR. The literature reports that miR-27b affects the function of MCP1 by acting on certain target genes in myocardial cells (Chinchilla et al, 2011;Wang et al, 2012), but there have been no reports on whether miR-27b downregulates the expression of MCP1 and is involved in the occurrence and development of VMC. Therefore, in this study, we used IL-17 to induce the upregulation of MCP1 expression, then up-regulated the content of miR-27b by transiently transfecting H9C2 cells with miR-27b mimics.…”

MicroRNAs Are Involved in End-Organ Damage During Hypertension

“…54 Mitogenactivated protein kinase, which is regulated by miR-21 in fibroblasts, is under the control of miR-142. 55 Others report that both miR-221 56 and miR-27b 57 promote cardiac hypertrophy, whereas miR-206 attenuates cardiac remodeling by inhibiting metalloproteinase inhibitor 3.…”