Substitution of the SERCA2 Cys(674) reactive thiol accelerates atherosclerosis by inducing endoplasmic reticulum stress and inflammation

作者全名："Su, Hang; Mei, Yu; Luo, Shuangxue; Wu, Haixia; He, Yan; Shiraishi, Yasunaga; Hu, Pingping; Cohen, Richard A.; Tong, Xiaoyong"

作者地址："[Su, Hang; Luo, Shuangxue; Wu, Haixia; He, Yan; Hu, Pingping; Tong, Xiaoyong] Chongqing Univ, Sch Pharmaceut Sci, Chongqing Key Lab Nat Prod Synth & Drug Res, Chongqing 401331, Peoples R China; [Mei, Yu; Cohen, Richard A.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Vasc Biol Sect, Boston, MA 02118 USA; [Shiraishi, Yasunaga] Natl Def Med Coll, Dept Internal Med, Div Cardiovasc Med, Saitama, Japan; [Hu, Pingping] Chongqing Med Univ, Coll Pharm, Chongqing 400016, Peoples R China"

通信作者："Tong, XY (通讯作者)，Chongqing Univ, Sch Pharmaceut Sci, Chongqing Key Lab Nat Prod Synth & Drug Res, Chongqing 401331, Peoples R China.; Hu, PP (通讯作者)，Chongqing Med Univ, Coll Pharm, Chongqing 400016, Peoples R China."

来源：BRITISH JOURNAL OF PHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:000828502600001

JCR分区：Q1

影响因子：7.3

年份：2022

卷号：179

期号：20

开始页：4778

结束页：4791

文献类型：Article

关键词：atherosclerosis; endoplasmic reticulum stress; inflammation; macrophages; SERCA2

摘要："Background and Purpose The cysteine(674) (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."

基金机构："National Natural Science Foundation of China [81700237, 31571172, 81870343]; Chongqing Natural Science Foundation [cstc2021jcyj-msxmX0043]; Chongqing Research Program of Basic Research and Frontier Technology [cstc2016jcyjA0407]; Fundamental Research Funds for the Central Universities [2018CDQYYX0042]; National Institutes of Health [HL31607]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (81700237, Hu P; 31571172, 81870343, Tong X), Chongqing Natural Science Foundation (cstc2021jcyj-msxmX0043, X.T.); Chongqing Research Program of Basic Research and Frontier Technology (cstc2016jcyjA0407, Tong X), Fundamental Research Funds for the Central Universities (2018CDQYYX0042, Tong X), and National Institutes of Health grant (HL31607, Tong X, and Cohen RA)."