Abstract Body (Do not enter title and authors here): Background: Atherosclerosis is partly caused by the infiltration of inflammatory cells into vascular wall, leading to enhanced inflammation and lipid accumulation. Recent studies showed that S100A12 activated inflammation in various experimental autoimmune disease models.
Hypothesis: Given the pivotal role that macrophages play in fueling atherosclerosis, it remains an significant question whether and how myeloid-specific S100A12 promotes atherogenesis.
Aims: This study was to evaluate the impact of S100A12 on regulating macrophage function during atherosclerosis.
Methods: We analyzed S100A12 levels in the plasma of coronary artery disease (CAD) patients (n=253) and non-CAD individuals (n=217), as well as in coronary artery atherosclerotic plaques (n=15) and non-atherosclerotic coronary samples (n=10). Using myeloid-specific S100A12 transgenic mice (Lyz-SA) on the Apoe^-/- background, we evaluated the cellular sources of S100A12 and its biological effects both in vitro and in vivo after 16 weeks of Western diet. RNA interference technology was used to knock down RAGE, FoxO1, and PDCD4 in vivo.
Results: S100A12 levels were significantly higher in plasma, atherosclerotic plaques, and PBMCs from CAD patients compared to controls, and were associated with CAD severity. Macrophages were identified as the primary source of S100A12 in human coronary atherosclerotic plaques. Lyz-SA/Apoe^-/- mice exhibited enhanced atherosclerotic lesion formation, increased immune and inflammatory cell content in aorta, and an aggravation of necrotic core content in aortic root sections. Mechanistically, we found myeloid cell-specific S100A12 exacerbated the atherosclerotic lesion size and modulated local and systemic inflammatory responses via upregulation of RAGE-FoxO1-PDCD4 pathway. PDCD4 siRNA abolished NF-κB-induced changes in macrophage-mediated local and systemic inflammatory responses. Tranilast, which blocked the interaction between S100A12 and RAGE, reduced vascular inflammation and alleviated plaque regression or prevented the progression of established atherosclerosis compared to Apoe^-/- mice.
Conclusions: Collectively, these findings suggest that myeloid-specific S100A12 promotes atherogenesis by facilitating the recruitment of pro-inflammatory macrophages through activation of the RAGE-FoxO1-PDCD4 signaling pathway. Targeting S100A12 in macrophages may represent a novel therapeutic strategy for treating atherosclerosis.