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

Abstract

Aims Aging impairs cardiac function and increases susceptibility to myocardial ischemic 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 downregulated matrix metalloprotease (MMP)2/16 expression in cardiomyocytes. This downregulation 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 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.

METTL14-mediated N6-methyladenosine modification induces the ferroptosis of hypoxia/reoxygenation-induced cardiomyocytes

“…Troxerutin-induced repression of miR-146a-5p moderates cardiomyocyte apoptosis in myocardial I/R injury [ 28 ], whereas miR-146a-5p upregulation by silencing of long noncoding RNA SRY-box transcription factor 2 overlapping transcript also contributes to the remission of this disease [ 29 ]. Intriguingly, miR-146a-5p can mediate a compensatory regulation that protects cardiac function after MI, but this compensatory regulation is supposed to be inhibited by aging, leading to elevated susceptibility to myocardial I/R injury [ 58 ]. Based on our results, the total m6A was increased after H/R treatment, which may be due to METTL14-mediated m6A modification on pri-miR-146a-5p.…”

M2 macrophage‑derived exosomes alleviate KCa3.1 channel expression in rapidly paced HL‑1 myocytes via the NF‑κB (p65)/STAT3 signaling pathway

“…Previous studies have reported that upregulating miR-146a-5p expression in cardiosphere-derived cells inhibits the production of proinflammatory cytokines and transcripts, hence reducing myocardial fibrosis ( 25 ). Additionally, miR-146a-5p carried by exosomes was reported to downregulate matrix metalloprotease 2/16 expression in cardiomyocytes, which could improve cardiac contractile function and decrease susceptibility after myocardial infarction ( 26 ). Furthermore, a decreased miR-146a-5p level was linked to an increased risk of non-stroke severe adverse cardiovascular events in AF ( 27 ).…”