S100A12 triggers NETosis to aggravate myocardial infarction injury via the Annexin A5-calcium axis

Xi Zhang, Haixu Song, Dan Liu, Yi Cai, Ziqi Liu, Xiaolin Zhang, Xiaojie Zhao, Yan Zhang, Quanmin Jing, Chenghui Yan () and Yaling Han ()
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Xi Zhang: General Hospital of Northern Theater Command
Haixu Song: General Hospital of Northern Theater Command
Dan Liu: General Hospital of Northern Theater Command
Yi Cai: General Hospital of Northern Theater Command
Ziqi Liu: General Hospital of Northern Theater Command
Xiaolin Zhang: General Hospital of Northern Theater Command
Xiaojie Zhao: General Hospital of Northern Theater Command
Yan Zhang: General Hospital of Northern Theater Command
Quanmin Jing: General Hospital of Northern Theater Command
Chenghui Yan: General Hospital of Northern Theater Command
Yaling Han: General Hospital of Northern Theater Command

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Neutrophil extracellular traps (NETs) play a critical role in acute myocardial infarction (AMI) and the externalization of S100 family members. Here, we show the effects of S100A12 on NETs formation and myocardial injury following AMI. S100A12 expression increases rapidly in neutrophils and peaks on day 1 after AMI, promoting NETs production and exacerbating myocardial injury. DNase I, an inhibitor of NETs, reduces apoptosis of cardiomyocytes induced by S100A12. Mechanistically, the interaction of S100A12 and Annexin A5 (ANXA5) enhances calcium influx and promotes NETs formation. Blockage of ANXA5 effectively attenuates heart function impairment after AMI. Finally, we show that plasma S100A12 levels correlate with dsDNA concentration, and this correlation is associated with an increased risk of all-cause mortality during the 1-year follow-up of AMI patients. These findings, derived from male mice, reveal the S100A12-ANXA5-calcium influx axis as a potential therapeutic target and biomarker for AMI.

Date: 2025
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DOI: 10.1038/s41467-025-56978-5

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