Substitution of SERCA2 Cys674 accelerates aortic aneurysm by inducing endoplasmic reticulum stress and promoting cell apoptosis

Background and purpose: The Cys⁶⁷⁴ residue (C674) in the sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2 (SERCA2) is key to maintaining its Enzyme activity. The irreversible oxidation of C674 occurs broadly in aortic aneurysms. Substitution of C674 promotes a phenotypic transition of aortic smooth muscle cells (SMCs) and exacerbates angiotensin II-induced aortic aneurysm. However, its underlying mechanism remains enigmatic.

Experimental approach: Heterozygous SERCA2 C674S knock-in (SKI) mice, in which half of C674 was replaced by serine, were used to mimic partially irreversible oxidation of C674 thiol. The aortas of SKI mice and their littermate wild-type mice under an LDL receptor-deficient background were collected for histological and immunohistochemical analysis. Cultured aortic SMCs were used for protein expression, Apoptosis analysis, and cell function studies.

Key results: The substitution of SERCA2 C674 caused endoplasmic reticulum (ER) stress and induced SMC Apoptosis. The inhibition of ER stress by 4-phenylbutyric acid (4-PBA) in SKI aortic SMCs decreased the expression of marker proteins for cell Apoptosis as well as phenotypic transition, and prevented cell Apoptosis, proliferation, migration, and macrophage adhesion to SMCs. 4-PBA also ameliorated angiotensin II-induced aortic aneurysm in SKI mice.

Conclusions and implications: The irreversible oxidation of SERCA2 C674 promotes the development of aortic aneurysm by inducing ER stress and subsequent SMC Apoptosis. Our study illustrates that ER stress caused by oxidative inactivation of C674 is related to the pathogenesis of aortic aneurysm. Therefore, ER stress and SERCA2 are potential therapeutic targets for treating aortic aneurysm.