Impaired regulation of MMP2/16-MLCK3 by miR-146a-5p increased susceptibility to myocardial ischaemic injury in aging mice

Dong, Ming1,2; Chen, Dishen2; Zhu, Yanxia1; Yang, Shu3; Kumar, Santosh1; Zhang, Rui1; Zhou, Yin2; Yang, Ziyi1; Zheng, Na1; Zhu, Ting1; Xiang, Jiaqing1; Liu, Yun4; Kang, Lin3,5; Liu, Jie1

2022-06-01

10.1093/cvr/cvac104

CARDIOVASCULAR RESEARCH   Impact Factor & Quartile

0008-6363

1755-3245

["Aims Aging impairs cardiac function and increases susceptibility to myocardial ischaemic injury. Cardiac myosin light chain kinase (MLCK3) phosphorylates cardiac myosin regulatory light chain (MLC2), controlling sarcomere organization and cardiomyocyte contraction. Dysregulation of MLCK3 and phosphorylated MLC2 (p-MLC2) contributes to heart failure after myocardial infarction (MI). We aimed at exploring how the MLCK3-p-MLC2 axis changes in aging hearts post MI and at investigating the underlying regulatory mechanisms.","Methods and results We generated adult (3 months) and aged (30 months) MI mouse models to compare their cardiac performance, and then detected MLCK3 expression and MLC2 activity. Aging increased the size of MI-induced infarctions and promoted cardiac contractile dysfunction. Furthermore, MLCK3 expression and MLC2 activity increased in adult hearts after MI, but not in aged hearts. miR-146a was found consistently increased in adult and aged hearts post MI. Mechanistic analyses performed in vitro demonstrated that miR-146a-5p down-regulated matrix metalloprotease (MMP)2/16 expression in cardiomyocytes. This down-regulation in turn increased MLCK3 expression and MLC2 activity. However, miR-146a-5p failed to regulate the MMP2/16-MLCK3-p-MLC2 axis in senescent cardiomyocytes or in cardiac miR-146a conditional knockout mice, with the latter experiencing an exacerbated deterioration of cardiac function post MI.","Conclusion These results suggest that an increase of MLCK3 and p-MLC2 contents through decreasing MMP2/16 by miR-146a-5p represents a compensatory mechanism that can protect cardiac contractile function after MI. Aging impairs this miR-146a-5p-regulated MMP2/16-MLCK3-p-MLC2 contractile axis, leading to compromised contractile function and increased susceptibility to heart failure.","[GRAPHICS]","."]

Aging heart miR-146a MMP2/16 MLCK3 Myocardial infarction

SCI

English

Corresponding

Start-up Foundation of Guangzhou National Laboratory[YW-JCZD0101] ; National Natural Science Foundation of China[81970250] ; National Science Foundation of Guangdong Province["2022A1515012310","2021A1515010787"] ; Shenzhen Key Laboratory of Metabolism and Cardiovascular Homeostasis[ZDSYS20190902092903237] ; Basic Research Foundation of Shenzhen["JCYJ20210324094006018","JCYJ20180508152222104"]

Cardiovascular System & Cardiology

Cardiac & Cardiovascular Systems

WOS:000826843200001

OXFORD UNIV PRESS

CLINICAL MEDICINE

Web of Science

1.Shenzhen Univ, Hlth Sci Ctr, Dept Pathophysiol, Guangdong Key Lab Genome Stabil & Human Dis Preve, 1066 Xueyuan Ave, Shenzhen 518060, Peoples R China
2.Guangzhou Lab, Guangzhou 510005, Guangdong, Peoples R China
3.Jinan Univ, Shenzhen Peoples Hosp, Clin Med Coll 2, Dept Geriatr, Shenzhen, Peoples R China
4.Sun Yat Sen Univ, Affiliated Hosp 7, Guangzhou, Guangdong, Peoples R China
5.Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Biobank Natl Innovat Ctr Adv Med Devices, Shenzhen, Peoples R China

Dong, Ming,Chen, Dishen,Zhu, Yanxia,et al. Impaired regulation of MMP2/16-MLCK3 by miR-146a-5p increased susceptibility to myocardial ischaemic injury in aging mice[J]. CARDIOVASCULAR RESEARCH,2022.

Dong, Ming.,Chen, Dishen.,Zhu, Yanxia.,Yang, Shu.,Kumar, Santosh.,...&Liu, Jie.(2022).Impaired regulation of MMP2/16-MLCK3 by miR-146a-5p increased susceptibility to myocardial ischaemic injury in aging mice.CARDIOVASCULAR RESEARCH.

Dong, Ming,et al."Impaired regulation of MMP2/16-MLCK3 by miR-146a-5p increased susceptibility to myocardial ischaemic injury in aging mice".CARDIOVASCULAR RESEARCH (2022).