S100a12 Aggravates Acute Myocardial Infarction Injury Through Excessive Neutrophil Extracellular Trap Formation

Introduction: S100A12 represents a novel biomarker and therapeutic target that regulates cardiovascular disease after its release from myeloid cells. However, the role of S100A12 in the etiology of Acute Myocardial Infarction (AMI) is not well understood. Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of AMI and in the externalization of some S100 family members. Here, we investigated the effect of S100A12 on neutrophils’ function and myocardial injury after AMI. Methods and Results: Since S100A12 is a human specific molecule and not expressed in mice, we constructed transgenic (TG) mice expressing S100A12 in myeloid cells. By left anterior descending artery ligation and flow cytometry, we found that S100A12 markedly increased neutrophil infiltration and myocardial injury in TG mice compared to WT mice. Within the infarct zone, more neutrophil extracellular traps (NETs) were observed in TG mice, whereas intraperitoneal injection of DNase I decreased the damage effect of NETs. We used the overexpressing plasmid of S100A12 and observed that S100A12 enhanced the level of NETosis. Whereas, siRNA-mediated S100A12 silencing reduced the production of NETs. By ChIP and dual-luciferase reporter assay we found that Hypoxia-inducible factor-1α (HIF1α) directly bound to the promoter of the S100A12 gene and regulated S100A12 expression. We next used tandem mass tag (TMT) labeling quantitative proteomic technology and discovered that annexin a5 (ANXA5) was a receptor with significantly different expression level in TG compared with WT mice. Finally, we demonstrated that S100A12 increased NETs formation via receptor RAGE and ANXA5. Conclusions: Our findings reveal a critical role of S100A12 in regulating neutrophil activation and NETs formation, resulting in aggravated myocardial injury after AMI. In such a process, S100A12 regulates NETosis via the Hif1α-S100A12-ANXA5/RAGE pathway. S100A12 is a useful molecular marker and possible target for treatment for AMI.