肌浆网/内质网钙ATP酶2(SERCA2)674位的半胱氨酸(C674)是调控SERCA2活性维持钙稳态的关键谷胱甘肽化位点。C674的不可逆氧化在人和小鼠的主动脉瘤中增加，其是否参与了主动脉瘤的进程尚无报道。利用SERCA2的C674S基因突变敲入小鼠(SKI)来模拟这一位点的不可逆性氧化对谷胱甘肽化的抑制，我们发现血管紧张素Ⅱ诱导的腹主动脉瘤在SKI中加剧。在SKI的主动脉平滑肌细胞：内质网应激及凋亡相关蛋白表达增加；钙依赖NFAT转录通路激活；合成型和炎性标志物表达增加而收缩型标志物表达减少；调控细胞转型的PPARγ表达降低；细胞的增殖和爬行能力增强。我们的课题假说是：C674的不可逆性氧化干扰钙稳态，诱导内质网应激和激活钙依赖转录通路，调控平滑肌细胞转型、凋亡和炎性反应，促进腹主动脉瘤的形成。本项目将明确C674的不可逆性氧化促进主动脉瘤形成的机制，为改善主动脉瘤提供干预靶点。

Cysteine 674 (C674) at sarco/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) is the key cysteine for glutathiolation to stimulate SERCA2 activity and to maintain calcium homeostasis. The irreversible oxidation of C674 is increased in both human and mouse aortic aneurysms, and its contribution to the development of aortic aneurysms has not been reported. Using a SERCA2 C674S knock-in mouse (SKI) to mimic the irreversible oxidation of cysteine 674 that prevents its glutathiolation, we found that the angiotensin Ⅱ-induced abdominal aortic aneurysms were accelerated in SKI. Compared with aortic smooth muscle cells from wild type, the ones from SKI had increased expression levels of endoplasmic reticulum stress markers and apoptosis related proteins. The intracellular calcium dependent NFAT transcriptional pathways were activated in SKI. The expression levels of both smooth muscle synthetic markers and inflammatory markers were increased, while the expression levels of contractile markers were decreased in SKI. PPARγ, which controls SMC phenotypic switch, its expression was decreased in SKI. Both cell proliferation rate and migration rate were increased in SKI. Our hypothesis is that the irreversible oxidation of SERCA2 at cysteine 674 disturbs calcium homeostasis to induce endoplasmic reticulum stress and to activate intracellular calcium dependent transcriptional pathways, which mediate smooth muscle cell phenotypic switch, apoptosis, and inflammation, and to accelerate abdominal aortic aneurysm. This project is to clarify the irreversible oxidation of C674 at SERCA2 in the development of aortic aneurysm and the underlying mechanisms involved, which will inform the development of therapeutic interventions to improve aortic aneurysm.