N6-methyladenosine (m6A) methylation plays an important role in myocardial infarction, which is related to cardiomyocyte pyroptosis. This study aimed to explore the effects of the m6A methyltransferase, METTL14, on pyroptosis and the underlying mechanisms.
Materials and methods
The role of METTL14 in vivo was assessed by TTC staining, biochemical indicators, and H&E assays. Cell pyroptosis was evaluated by PI staining, IF, and western blot assay. The m6A methylation of NLRP3 was evaluated by RIP, dual-luciferase reporter assay, Me-RIP, and stability test.
Results
The results indicated that METTL14 was highly expressed in LAD-ligated mice and OGD-induced cardiomyocytes. Depletion of METTL14 inhibited OGD-induced pyroptosis of cardiomyocytes and suppressed myocardial injury. Mechanically, METTL14 promoted m6A methylation of NLRP3 to enhance mRNA stability. Overexpression of NLRP3 reversed the effects of METTL14 knockdown on pyroptosis.
Conclusions
METTL14 knockdown attenuated cardiomyocyte pyroptosis and myocardial infarction by suppressing NLRP3 m6A methylation. The findings suggested that METTL14 has the potential to be the therapeutic target of myocardial infarction.
DavodianLWLarsenJKPPovlsenAL, et al.Timing and causes of death in acute myocardial infarction complicated by cardiogenic shock (from the RETROSHOCK cohort). Am J Cardiol2022; 171: 15–22.
2.
MurphyAGoldbergS. Mechanical complications of myocardial infarction. Am J Med2022; 135: 1401–1409.
3.
ZhuFMengQYuY, et al.Adult cardiomyocyte proliferation: a new insight for myocardial infarction therapy. J Cardiovasc Transl Res2021; 14: 457–466.
4.
SaitoYOyamaKTsujitaK, et al.Treatment strategies of acute myocardial infarction: updates on revascularization, pharmacological therapy, and beyond. J Cardiol2023; 81: 168–178.
5.
Markman FilhoBLimaSG. Coronary reperfusion in acute myocardial infarction: trying the optimal. Executing the Possible. Arq Bras Cardiol2021; 117: 130–131.
6.
LindseyMLBruntKRKirkJA, et al.Guidelines for in vivo mouse models of myocardial infarction. Am J Physiol Heart Circ Physiol2021; 321: H1056–H1h73.
7.
FlamandMNTegowskiMMeyerKD. The proteins of mRNA modification: writers, readers, and erasers. Annu Rev Biochem2023; 92: 145–173.
8.
JiangXLiuBNieZ, et al.The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther2021; 6: 74.
9.
KumariRRanjanPSuleimanZG, et al.mRNA modifications in cardiovascular biology and disease: with a focus on m6A modification. Cardiovasc Res2022; 118: 1680–1692.
10.
VausortMNiedolistekMLumleyAI, et al.Regulation of N6-methyladenosine after myocardial infarction. Cells2022; 11: 2271.
11.
YangJShangguanQXieG, et al.M6a regulator methylation patterns and characteristics of immunity in acute ST-segment elevation myocardial infarction. Sci Rep2023; 13: 15688.
12.
ChenJFangYXuY, et al.Role of m6A modification in female infertility and reproductive system diseases. Int J Biol Sci2022; 18: 3592–3604.
13.
ZhouHYinKZhangY, et al.The RNA m6A writer METTL14 in cancers: roles, structures, and applications. Biochim Biophys Acta Rev Cancer2021; 1876: 188609.
14.
XiangQYiXZhuXH, et al.Regulated cell death in myocardial ischemia-reperfusion injury. Trends Endocrinol Metab2024; 35: 219–234.
ChaiRYeZXueW, et al.Tanshinone IIA inhibits cardiomyocyte pyroptosis through TLR4/NF-κB p65 pathway after acute myocardial infarction. Front Cell Dev Biol2023; 11: 1252942.
17.
MatschkeKJungF. Regulation of the myocardial microcirculation. Clin Hemorheol Microcirc2008; 39: 265–279.
18.
LiCJiaYRGouQ, et al.Connexin 43 regulates pyroptosis by influencing intracellular calcium levels in X-ray induced vascular endothelial cell damage. Clin Hemorheol Microcirc2024; 88: 485–497.
19.
GaoJGaoZ. The regulatory role and mechanism of USP14 in endothelial cell pyroptosis induced by coronary heart disease. Clin Hemorheol Microcirc2024; 86: 495–508.
20.
BaiCWangJLiJ. Transcription factor GATA1 represses oxidized-low density lipoprotein-induced pyroptosis of human coronary artery endothelial cells. Clin Hemorheol Microcirc2023; 83: 81–92.
21.
KordiNSanaeiMAkraminiaP, et al.PANoptosis and cardiovascular disease: the preventive role of exercise training. Clin Hemorheol Microcirc2024; 88: 499–512.
22.
ZhaolinZGuohuaLShiyuanW, et al.Role of pyroptosis in cardiovascular disease. Cell Prolif2019; 52: e12563.
23.
ToldoSAbbateA. The NLRP3 inflammasome in acute myocardial infarction. Nat Rev Cardiol2018; 15: 203–214.
24.
ChenLLiSZhuJ, et al.Mangiferin prevents myocardial infarction-induced apoptosis and heart failure in mice by activating the Sirt1/FoxO3a pathway. J Cell Mol Med2021; 25: 2944–2955.
25.
WangKLiYQiangT, et al.Role of epigenetic regulation in myocardial ischemia/reperfusion injury. Pharmacol Res2021; 170: 105743.
26.
LiLXuNLiuJ, et al.M6a methylation in cardiovascular diseases: from mechanisms to therapeutic potential. Front Genet2022; 13: 908976.
27.
LiuWShenJLiY, et al.Pyroptosis inhibition improves the symptom of acute myocardial infarction. Cell Death Dis2021; 12: 852.
28.
ShiLLiXZhangM, et al.Downregulation of wtap causes dilated cardiomyopathy and heart failure. J Mol Cell Cardiol2024; 188: 38–51.
29.
HanZWangXXuZ, et al.ALKBH5 Regulates cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1. Theranostics2021; 11: 3000–3016.
30.
MathiyalaganPAdamiakMMayourianJ, et al.FTO-Dependent N(6)-Methyladenosine regulates cardiac function during remodeling and repair. Circulation2019; 139: 518–532.
31.
GongRWangXLiH, et al.Loss of m(6)A methyltransferase METTL3 promotes heart regeneration and repair after myocardial injury. Pharmacol Res2021; 174: 105845.
32.
ToldoSMauroAGCutterZ, et al.Inflammasome, pyroptosis, and cytokines in myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol2018; 315: H1553–H1h68.
33.
FuJWuH. Structural mechanisms of NLRP3 inflammasome assembly and activation. Annu Rev Immunol2023; 41: 301–316.
34.
ToldoSMezzaromaEMauroAG, et al.The inflammasome in myocardial injury and cardiac remodeling. Antioxid Redox Signal2015; 22: 1146–1161.
35.
MauroAGBonaventuraAMezzaromaE, et al.NLRP3 Inflammasome in acute myocardial infarction. J Cardiovasc Pharmacol2019; 74: 175–187.
LanJXuBShiX, et al.WTAP-mediated N(6)-methyladenosine modification of NLRP3 mRNA in kidney injury of diabetic nephropathy. Cell Mol Biol Lett2022; 27: 51.
38.
QiuTWuCYaoX, et al.AS3MT Facilitates NLRP3 inflammasome activation by m(6)A modification during arsenic-induced hepatic insulin resistance. Cell Biol Toxicol2023; 39: 2165–2181.
39.
WangBLiuYJiangR, et al.Emodin relieves the inflammation and pyroptosis of lipopolysaccharide-treated 1321N1 cells by regulating methyltransferase-like 3 -mediated NLR family pyrin domain containing 3 expression. Bioengineered2022; 13: 6740–6749.
40.
YuHLiQSGuoJN, et al.METTL14-mediated m(6)A methylation of pri-miR-5099 to facilitate cardiomyocyte pyroptosis in myocardial infarction. Acta Pharmacol Sin2025; 46: 1639–1651.
