Substitution of the SERCA2 Cys⁶⁷⁴ reactive thiol accelerates atherosclerosis by inducing endoplasmic reticulum stress and inflammation

Abstract

Background and Purpose The cysteine674 (C674) thiol of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 is easily and irreversibly oxidized under atherosclerotic conditions. However, the contribution of the C674 thiol redox status in the development of atherosclerosis remains unclear. Our goal was to elucidate the possible mechanism involved. Experimental Approach Heterozygous SERCA2 C674S knock‐in mice in which half of the C674 was substituted by serine (S674) were used to mimic the removal of the reactive C674 thiol, which occurs under pathological conditions. Bone marrow‐derived macrophages (BMDMs) and cardiac endothelial cells (ECs) were used for intracellular Ca2+, macrophage adhesion, and protein expression analysis. The whole aorta and aortic root were isolated for histological analysis. Key Results Cell culture studies suggest the partial substitution of SERCA2 C674 increased intracellular Ca2+ levels and induced ER stress in both BMDMs and ECs. The release of proinflammatory factors and macrophage adhesion increased in SKI BMDMs. In ECs, overexpression of S674 induced endothelial inflammation and promoted macrophage recruitment. SKI mice developed more severe atherosclerotic plaque and macrophage accumulation. Additionally, 4‐phenyl butyric acid, an ER stress inhibitor, suppressed ER stress and inflammatory responses in BMDMs and ECs, and alleviated atherosclerosis in SKI mice. Conclusions and Implications The substitution of SERCA2 C674 thiol accelerates the development of atherosclerosis by inducing ER stress and inflammation. Our findings highlight the importance of SERCA2 C674 redox state in the context of atherosclerosis and open up a novel therapeutic strategy to combat atherosclerosis.

Theaflavin-3,3′-digallate alleviates glucolipotoxicity-induced insulin secretion dysfunction in pancreatic β-TC-6 cells and zebrafish via anti-ferroptotic mechanisms by activating SERCA2

“…SERCA2 plays a central role in the maintenance of intracellular Ca 2+ homeostasis, insulin biosynthesis and survival in β cells. SERCA2 dysfunction has been reported to cause ER stress in various cells and tissues, including adipocytes, cardiomyocytes, kidney and muscles [55][56][57][58]. In this work, TF3 significantly increased SERCA2 expression in PA-treated β cells (Fig.…”