Premium
Substitution of the SERCA2 Cys 674 reactive thiol accelerates atherosclerosis by inducing endoplasmic reticulum stress and inflammation
Author(s) -
Su Hang,
Mei Yu,
Luo Shuangxue,
Wu Haixia,
He Yan,
Shiraishi Yasunaga,
Hu Pingping,
Cohen Richard A.,
Tong Xiaoyong
Publication year - 2022
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15912
Subject(s) - endoplasmic reticulum , proinflammatory cytokine , unfolded protein response , inflammation , chemistry , macrophage , oxidative stress , intracellular , microbiology and biotechnology , biochemistry , medicine , biology , in vitro
Background and Purpose The cysteine 674 (C674) thiol of sarcoplasmic/endoplasmic reticulum Ca 2+ 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 Ca 2+ , 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 Ca 2+ 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.