PMID- 35752105
OWN - NLM
STAT- MEDLINE
DCOM- 20220719
LR  - 20220726
IS  - 2352-3964 (Electronic)
IS  - 2352-3964 (Linking)
VI  - 81
DP  - 2022 Jul
TI  - Targeting miR-30d reverses pathological cardiac hypertrophy.
PG  - 104108
LID - S2352-3964(22)00289-4 [pii]
LID - 10.1016/j.ebiom.2022.104108 [doi]
LID - 104108
AB  - 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).
CI  - Copyright (c) 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
FAU - Li, Jin
AU  - Li J
AD  - 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.
FAU - Sha, Zhao
AU  - Sha Z
AD  - 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.
FAU - Zhu, Xiaolan
AU  - Zhu X
AD  - 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.
FAU - Xu, Wanru
AU  - Xu W
AD  - 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.
FAU - Yuan, Weilin
AU  - Yuan W
AD  - 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.
FAU - Yang, Tingting
AU  - Yang T
AD  - 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.
FAU - Jin, Bing
AU  - Jin B
AD  - 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.
FAU - Yan, Yuwei
AU  - Yan Y
AD  - 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.
FAU - Chen, Rui
AU  - Chen R
AD  - 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.
FAU - Wang, Siqi
AU  - Wang S
AD  - 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.
FAU - Yao, Jianhua
AU  - Yao J
AD  - Department of Cardiology, Tenth People's Hospital, School of Medicine, Tongji 
      University, Shanghai 200090, China.
FAU - Xu, Jiahong
AU  - Xu J
AD  - Department of Cardiology, Shanghai Tongji Hospital, School of Medicine, Tongji 
      University, Shanghai 200065, China.
FAU - Wang, Zitong
AU  - Wang Z
AD  - Department of Pathophysiology, Basic Medical Science, Harbin Medical University, 
      Harbin 150081, China.
FAU - Li, Guoping
AU  - Li G
AD  - Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical 
      School, Boston, MA 02114, USA.
FAU - Das, Saumya
AU  - Das S
AD  - Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical 
      School, Boston, MA 02114, USA.
FAU - Yang, Liming
AU  - Yang L
AD  - Department of Pathophysiology, Harbin Medical University-Daqing, Daqing, 163319, 
      China. Electronic address: limingyanghmu@163.com.
FAU - Xiao, Junjie
AU  - Xiao J
AD  - 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. Electronic address: junjiexiao@shu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20220622
PL  - Netherlands
TA  - EBioMedicine
JT  - EBioMedicine
JID - 101647039
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (MIRN30 microRNA, rat)
RN  - 0 (MIRN30d microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (Mirn30d microRNA, mouse)
RN  - 11128-99-7 (Angiotensin II)
RN  - EC 2.7.1.11 (MAP4K4 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - Angiotensin II/pharmacology
MH  - Animals
MH  - Cardiomegaly/genetics
MH  - China
MH  - *Heart Failure/genetics/metabolism
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/metabolism
MH  - Mice
MH  - *MicroRNAs/genetics/metabolism
MH  - Myocytes, Cardiac/metabolism
MH  - Protein Serine-Threonine Kinases
MH  - Rats
PMC - PMC9240797
OTO - NOTNLM
OT  - Pathological cardiac hypertrophy
OT  - Translational research
OT  - miR-30d
COIS- Declaration of interests Dr. Das is a founder of Switch Therapeutics, which did 
      not play any role in this study and has consulted for Amgen. The other authors 
      have declared that no conflict of interest exists.
EDAT- 2022/06/26 06:00
MHDA- 2022/07/20 06:00
PMCR- 2022/06/22
CRDT- 2022/06/25 18:28
PHST- 2022/03/27 00:00 [received]
PHST- 2022/05/29 00:00 [revised]
PHST- 2022/05/30 00:00 [accepted]
PHST- 2022/06/26 06:00 [pubmed]
PHST- 2022/07/20 06:00 [medline]
PHST- 2022/06/25 18:28 [entrez]
PHST- 2022/06/22 00:00 [pmc-release]
AID - S2352-3964(22)00289-4 [pii]
AID - 104108 [pii]
AID - 10.1016/j.ebiom.2022.104108 [doi]
PST - ppublish
SO  - EBioMedicine. 2022 Jul;81:104108. doi: 10.1016/j.ebiom.2022.104108. Epub 2022 Jun 
      22.