Targeting miR-30d reverses pathological cardiac hypertrophy

Jin Li; Zhao Sha; Xiaolan Zhu; Wanru Xu; Weilin Yuan; Tingting Yang; Bing Jin; Yuwei Yan; Rui Chen; Siqi Wang; Jianhua Yao; Jiahong Xu; Zitong Wang; Guoping Li; Saumya Das; Liming Yang; Junjie Xiao

EBioMedicine (Jul 2022)

Targeting miR-30d reverses pathological cardiac hypertrophy

Jin Li,
Zhao Sha,
Xiaolan Zhu,
Wanru Xu,
Weilin Yuan,
Tingting Yang,
Bing Jin,
Yuwei Yan,
Rui Chen,
Siqi Wang,
Jianhua Yao,
Jiahong Xu,
Zitong Wang,
Guoping Li,
Saumya Das,
Liming Yang,
Junjie Xiao

Affiliations

Jin Li: Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
Zhao Sha: Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
Xiaolan Zhu: Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
Wanru Xu: Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
Weilin Yuan: Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
Tingting Yang: Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
Bing Jin: Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
Yuwei Yan: Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
Rui Chen: Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
Siqi Wang: Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
Jianhua Yao: Department of Cardiology, Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200090, China
Jiahong Xu: Department of Cardiology, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China
Zitong Wang: Department of Pathophysiology, Basic Medical Science, Harbin Medical University, Harbin 150081, China
Guoping Li: Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Saumya Das: Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Liming Yang: Department of Pathophysiology, Harbin Medical University-Daqing, Daqing, 163319, China; Corresponding author at: Department of Pathophysiology, Harbin Medical University-Daqing, Daqing, 163319, China.
Junjie Xiao: Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China; Corresponding author at: Cardiac Regeneration and Ageing lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, 333 Nan Chen Road, Shanghai 200444, China.

Journal volume & issue: Vol. 81
p. 104108

Abstract

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Summary: Background: Pathological cardiac hypertrophy occurs in response to numerous stimuli and precedes heart failure (HF). Therapies that ameliorate pathological cardiac hypertrophy are highly needed. Methods: The 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. Findings: miR-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. Interpretation: Overexpression of miR-30d may be a potential approach to treat pathological cardiac hypertrophy. Funding: This 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).

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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