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MiR-217 Promotes Cardiac Hypertrophy and Dysfunction by Targeting PTEN.

ABSTRACT: Previously, we found that the miR-217 expression level was increased in hearts from chronic heart failure (CHF) patients by using miRNA profile analysis. This study aimed to explore the role of miR-217 in cardiac dysfunction. Heart tissue samples from CHF patients were used to detect miR-217 expression levels. A type 9 recombinant adeno-associated virus (rAAV9) was employed to manipulate miR-217 expression in mice with thoracic aortic constriction (TAC)-induced cardiac dysfunction. Cardiac structure and function were measured by echocardiography and invasive pressure-volume analysis. The expression levels of miR-217 were increased in hearts from both CHF patients and TAC mice. Overexpression of miR-217 in vivo aggravated pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction, whereas miR-217-TUD-mediated downregulation of miR-217 reversed these effects. PTEN was predicted and validated as a direct target of miR-217, and re-expression of PTEN attenuated miR-217-mediated cardiac hypertrophy and cardiac dysfunction. Importantly, cardiomyocyte-derived miR-217-containing exosomes enhanced proliferation of fibroblasts in vitro. All of these findings show that miR-217 participates in cardiac hypertrophy and cardiac fibrosis processes through regulating PTEN, which suggests a promising therapeutic target for CHF.

SUBMITTER: Nie X

PROVIDER: S-EPMC6005806 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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miR-217 Promotes Cardiac Hypertrophy and Dysfunction by Targeting PTEN.

Nie Xiang X Fan Jiahui J Li Huaping H Yin Zhongwei Z Zhao Yanru Y Dai Beibei B Dong Nianguo N Chen Chen C Wang Dao Wen DW

Molecular therapy. Nucleic acids 20180617

Previously, we found that the miR-217 expression level was increased in hearts from chronic heart failure (CHF) patients by using miRNA profile analysis. This study aimed to explore the role of miR-217 in cardiac dysfunction. Heart tissue samples from CHF patients were used to detect miR-217 expression levels. A type 9 recombinant adeno-associated virus (rAAV9) was employed to manipulate miR-217 expression in mice with thoracic aortic constriction (TAC)-induced cardiac dysfunction. Cardiac struc ...[more]

PMID: 30195764

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Project description:BackgroundPathological cardiac hypertrophy occurs in response to numerous stimuli and precedes heart failure (HF). Therapies that ameliorate pathological cardiac hypertrophy are highly needed.MethodsThe expression level of miR-30d was analyzed in hypertrophy models and serum of patients with chronic heart failure by qRT-PCR. Gain and loss-of-function experiments of miR-30d were performed in vitro. miR-30d gain of function were performed in vivo. Bioinformatics, western blot, luciferase assay, qRT-PCR, and immunofluorescence were performed to examine the molecular mechanisms of miR-30d.FindingsmiR-30d was decreased in both murine and neonatal rat cardiomyocytes (NRCMs) models of hypertrophy. miR-30d overexpression ameliorated phenylephrine (PE) and angiotensin II (Ang II) induced hypertrophy in NRCMs, whereas the opposite phenotype was observed when miR-30d was downregulated. Consistently, the miR-30d transgenic rat was found to protect against isoproterenol (ISO)-induced pathological hypertrophy. Mechanistically, methyltransferase EZH2 could promote H3K27me3 methylation in the promotor region of miR-30d and suppress its expression during the pathological cardiac hypertrophy. miR-30d prevented pathological cardiac hypertrophy via negatively regulating its target genes MAP4K4 and GRP78 and inhibiting pro-hypertrophic nuclear factor of activated T cells (NFAT). Adeno-associated virus (AAV) serotype 9 mediated-miR-30d overexpression exhibited beneficial effects in murine hypertrophic model. Notably, miR-30d was reduced in serum of patients with chronic heart failure and miR-30d overexpression could significantly ameliorate pathological hypertrophy in human embryonic stem cell-derived cardiomyocytes.InterpretationOverexpression of miR-30d may be a potential approach to treat pathological cardiac hypertrophy.FundingThis work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to J Xiao), National Natural Science Foundation of China (82020108002 to J Xiao, 81900359 to J Li), the grant from Science and Technology Commission of Shanghai Municipality (20DZ2255400 and 21XD1421300 to J Xiao, 22010500200 to J Li), Shanghai Sailing Program (19YF1416400 to J Li), the "Dawn" Program of Shanghai Education Commission (19SG34 to J Xiao), the "Chen Guang" project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (19CG45 to J Li).

Project description:RATIONALE:Abnormal SUMOylation has emerged as a characteristic of heart failure (HF) pathology. Previously, we found reduced SUMO1 (small ubiquitin-like modifier 1) expression and SERCA2a (sarcoplasmic reticulum Ca2+-ATPase) SUMOylation in human and animal HF models. SUMO1 gene delivery or small molecule activation of SUMOylation restored SERCA2a SUMOylation and cardiac function in HF models. Despite the critical role of SUMO1 in HF, the regulatory mechanisms underlying SUMO1 expression are largely unknown. OBJECTIVE:To examine miR-146a-mediated SUMO1 regulation and its consequent effects on cardiac morphology and function. METHODS AND RESULTS:In this study, miR-146a was identified as a SUMO1-targeting microRNA in the heart. A strong correlation was observed between miR-146a and SUMO1 expression in failing mouse and human hearts. miR-146a was manipulated in cardiomyocytes through AAV9 (adeno-associated virus serotype 9)-mediated gene delivery, and cardiac morphology and function were analyzed by echocardiography and hemodynamics. Overexpression of miR-146a reduced SUMO1 expression, SERCA2a SUMOylation, and cardiac contractility in vitro and in vivo. The effects of miR-146a inhibition on HF pathophysiology were examined by transducing a tough decoy of miR-146a into mice subjected to transverse aortic constriction. miR-146a inhibition improved cardiac contractile function and normalized SUMO1 expression. The regulatory mechanisms of miR-146a upregulation were elucidated by examining the major miR-146a-producing cell types and transfer mechanisms. Notably, transdifferentiation of fibroblasts triggered miR-146a overexpression and secretion through extracellular vesicles, and the extracellular vesicle-associated miR-146a transfer was identified as the causative mechanism of miR-146a upregulation in failing cardiomyocytes. Finally, extracellular vesicles isolated from failing hearts were shown to contain high levels of miR-146a and exerted negative effects on the SUMO1/SERCA2a signaling axis and hence cardiomyocyte contractility. CONCLUSIONS:Taken together, our results show that miR-146a is a novel regulator of the SUMOylation machinery in the heart, which can be targeted for therapeutic intervention.

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MiR-217 Promotes Cardiac Hypertrophy and Dysfunction by Targeting PTEN.

Publications

miR-217 Promotes Cardiac Hypertrophy and Dysfunction by Targeting PTEN.

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