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Background <p>Ischemia–reperfusion (I/R) injury is a severe disorder during revascularization therapy against acute myocardial infarction.</p> Objective <p>Our study aims to investigate the role and regulation mechanism of Annexin A1 (ANXA1) against I/R injury.</p> Results <p>Western blotting analysis showed that ANXA1 expression in rat cardiomyocytes (H9C2 cells) was notably decreased by oxygen–glucose deprivation/reperfusion (OGD/R) treatment. Meanwhile, the NLRP3 inflammasome activation accompanied by pyroptosis and inflammation was observed in H9c2 cells under OGD/R induction. Besides, overexpression or knockdown of ANXA1 dramatically inhibited or aggravated NLRP3-mediated pyroptosis and inflammation. Further investigations found that the m<sup>6</sup>A level of ANXA1 was upregulated by OGD/R, thus leading to decreased mRNA stability in H9C2 cells. FTO, a N6-methyladenosine (m<sup>6</sup>A) “eraser”, was downregulated in H9C2 cells by OGD/R and shown to increase the ANXA1 protein expression by demethylating mRNA in H9c2 cells under OGD/R induction. Moreover, knockdown FTO reversed the protection of ANXA1 against NLRP3-mediated pyroptosis and inflammation in OGD/R-induced H9C2 cells.</p> Conclusion <p>ANXA1 protects cardiomyocytes against I/R injury by alleviating NLRP3-mediated pyroptosis and inflammation via FTO-mediate demethylation. These findings innovatively suggest the therapeutic potential of ANXA1 for myocardial I/R injury.</p>

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The up-regulation of ANXA1 by FTO-dependent demethylation alleviates NLRP3-mediated pyroptosis and inflammation in myocardial ischemia–reperfusion injury

  • 期刊论文

  • 发表日期：

    2025年2月15日

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  • Chaojie He,
  • Hongyan Fan,
  • Chunyan Zhu,
  • Yueqing Huang

摘要

Background

Ischemia–reperfusion (I/R) injury is a severe disorder during revascularization therapy against acute myocardial infarction.

Objective

Our study aims to investigate the role and regulation mechanism of Annexin A1 (ANXA1) against I/R injury.

Results

Western blotting analysis showed that ANXA1 expression in rat cardiomyocytes (H9C2 cells) was notably decreased by oxygen–glucose deprivation/reperfusion (OGD/R) treatment. Meanwhile, the NLRP3 inflammasome activation accompanied by pyroptosis and inflammation was observed in H9c2 cells under OGD/R induction. Besides, overexpression or knockdown of ANXA1 dramatically inhibited or aggravated NLRP3-mediated pyroptosis and inflammation. Further investigations found that the m6A level of ANXA1 was upregulated by OGD/R, thus leading to decreased mRNA stability in H9C2 cells. FTO, a N6-methyladenosine (m6A) “eraser”, was downregulated in H9C2 cells by OGD/R and shown to increase the ANXA1 protein expression by demethylating mRNA in H9c2 cells under OGD/R induction. Moreover, knockdown FTO reversed the protection of ANXA1 against NLRP3-mediated pyroptosis and inflammation in OGD/R-induced H9C2 cells.

Conclusion

ANXA1 protects cardiomyocytes against I/R injury by alleviating NLRP3-mediated pyroptosis and inflammation via FTO-mediate demethylation. These findings innovatively suggest the therapeutic potential of ANXA1 for myocardial I/R injury.