ALKBH5 mediated m6A modification of NLRP3 promotes cardiomyocytes pyroptosis in mice with myocardial infarction
- VernacularTitle:ALKBH5介导NLRP3的m6A修饰促进心肌梗死小鼠心肌细胞焦亡
- Author:
Miao-miao ZHAI
1
;
Jian-jian YIN
1
;
Zhi-mo WANG
1
;
Yue-jiao ZHOU
1
;
Qing-wen YU
1
;
Pei WANG
1
;
Li-rong ZHANG
1
;
Sheng-na HAN
1
Author Information
- Publication Type:Journal Article
- Keywords: myocardial infarction; NLRP3 inflamma-some; ALKBH5; m6A modification; IGF2BP2; pyrop-tosis
- From: Chinese Pharmacological Bulletin 2025;41(3):434-444
- CountryChina
- Language:Chinese
- Abstract: Aim To investigate the effects of m6A demethylase ALKBH5 on cardiomyocytes pyroptosis in mice with myocardial infarction(MI).Methods The MI model of left anterior descending coronary artery ligation surgery was established by knocking down ALKBH5 using adeno-associated virus,and the hypox-ia model of mouse cardiomyocytes(HL-1)was estab-lished by knocking down small interfering RNA.The effects of ALKBH5 on the pyroptosis of MI mice and hypoxic HL-1 cells were observed.Subsequently,mechanism studies were conducted at the cellular lev-el,and the binding of ALKBH5 and IGF2BP2 to NL-RP3 mRNA was detected through RNA pull down and RNA immunoprecipitation(RIP)experiments.The MeRIP-qPCR method was used to determine the effects of ALKBH5 on the mRNA m6A level of NLRP3.Acti-nomycin D for RNA stability experiments were conduc-ted to detect the effects of ALKBH5 and IGF2BP2 on the stability of NLRP3 mRNA.Results Knocking down ALKBH5 in vivo and in vitro both inhibited NL-RP3 inflammasome activation and alleviated pyroptosis in MI mice and hypoxic HL-1 cells.Mechanistically,the results showed that NLRP3 mRNA could bind to ALKBH5 protein in HL-1 cells;knocking down ALK-BH5 could increase the m6A level of NLRP3 and re-duce the stability of NLRP3 mRNA;subsequently,it was confirmed that NLRP3 mRNA and IGF2BP2 pro-tein bound to each other;knocking down IGF2BP2 in-creased the mRNA stability of NLRP3.The Rescue ex-periment showed that knocking down IGF2BP2 re-versed the decrease in NLRP3 mRNA expression caused by knocking down ALKBH5.Conclusions ALKBH5 mediated m6A modification of NLRP3 pro-motes cardiomyocytes pyroptosis in mice with myocardi-al infarction.
