S100A12 mediates aortic wall remodeling and aortic aneurysm.
S100A12 mediates aortic wall remodeling and aortic aneurysm.
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DOI：
10.1161/circresaha.109.209486
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发表时间：
2010-01-08
影响因子：
20.1
通讯作者：
McNally EM
中科院分区：
文献类型：
--
作者：
Hofmann Bowman M;Wilk J;Heydemann A;Kim G;Rehman J;Lodato JA;Raman J;McNally EM
S100 A12是一种小的钙结合蛋白，是晚期糖基化终产物受体（Receptor for Advanced Glycation End Products，RECEPTOR）的配体。S100 A12与动脉粥样硬化等炎症状态密切相关，但S100 A12作为其配体的作用尚不清楚。为了测试S100 A12在血管炎症中的作用，我们产生并分析了在SM 22 α启动子控制下在血管平滑肌中表达人S100 A12的小鼠，因为S100 A12在小鼠中不存在。转基因小鼠表现出病理性血管重塑，主动脉中膜异常增厚，弹性纤维紊乱，胶原沉积增加，潜伏性MMP-2蛋白增加，平滑肌应力纤维减少，导致主动脉进行性扩张。在原代培养的主动脉平滑肌细胞中，我们发现S100 A12介导IL-6的产生增加，TGF β途径的激活和代谢活性的增加，氧化应激增强。为了将我们的发现与人类主动脉瘤性疾病相关联，我们检测了胸主动脉瘤患者主动脉组织中S100 A12的表达，发现血管平滑肌细胞中S100 A12的表达增加。S100 A12表达足以通过调节体内氧化应激、炎症和血管重塑来激活致病途径。
S100A12 is a small calcium binding protein that is a ligand of the Receptor for Advanced Glycation End products (RAGE). RAGE has been extensively implicated in inflammatory states such as atherosclerosis, but the role of S100A12 as its ligand is less clear. To test the role of S100A12 in vascular inflammation, we generated and analyzed mice expressing human S100A12 in vascular smooth muscle under control of the SM22α promoter since S100A12 is not present in mice. Transgenic mice displayed pathologic vascular remodeling with aberrant thickening of the aortic media, disarray of elastic fibers, and increased collagen deposition, together with increased latent MMP-2 protein and reduction in smooth muscle stress fibers leading to a progressive dilatation of the aorta. In primary aortic smooth muscle cell cultures, we found that S100A12-mediates increased IL-6 production, activation of TGF β pathways and increased metabolic activity with enhanced oxidative stress. To correlate our findings to human aortic aneurysmal disease, we examined S100A12 expression in aortic tissue from patients with thoracic aortic aneurysm and found increased S100A12 expression in vascular smooth muscle cells. S100A12 expression is sufficient to activate pathogenic pathways through the modulation of oxidative stress, inflammation and vascular remodeling in vivo.