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

Abstract

Background and Purpose: The Cys 674 residue (C674) in the sarcoplasmic/ endoplasmic reticulum Ca 2+ 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.

Cellular, Molecular and Clinical Aspects of Aortic Aneurysm—Vascular Physiology and Pathophysiology

“…Tissue degradation is also preceded by necroptosis and apoptosis in both TAA and AAA [25]. The progression of AAA is strictly related to the up-regulation of apoptotic markers, i.e., Cas3 [49]. Deregulated expressions of miRNA level, as miR-520f-3p, miR-155-5p and miR-1-3p, were proposed as transcriptional biomarkers of AAA disease, among others, leading to apoptosis [50][51][52].…”