CDN1163 alleviates SERCA2 dysfunction-induced pulmonary vascular remodeling by inhibiting the phenotypic transition of pulmonary artery smooth muscle cells

作者全名："Yu, Weimin; Zhang, Qian; Qiu, Yixiang; Chen, Hui; Huang, Xiaoyang; Xiao, Li; Xu, Gang; Li, Siqi; Hu, Pingping; Tong, Xiaoyong"

作者地址："[Yu, Weimin] Chinese Acad Sci, Inst Hlth Biol Chem Medicat, Chongqing Inst Green & Intelligent Technol, Chongqing, Peoples R China; [Yu, Weimin; Zhang, Qian; Qiu, Yixiang; Chen, Hui; Huang, Xiaoyang; Xiao, Li; Li, Siqi; Tong, Xiaoyong] Chongqing Univ, Sch Pharmaceut Sci, Chongqing, Peoples R China; [Xu, Gang] Third Mil Med Univ, Army Med Univ, Inst Med & Equipment High Altitude Reg, Coll High Altitude Mil Med, Chongqing, Peoples R China; [Xu, Gang] Peoples Liberat Army, Key Lab High Altitude Med, Chongqing, Peoples R China; [Li, Siqi] Monash Univ, Cent Clin Sch, Melbourne, Australia; [Hu, Pingping] Chongqing Med Univ, Coll Pharm, Chongqing, Peoples R China; [Tong, Xiaoyong] Jinfeng Lab, Chongqing, Peoples R China; [Tong, Xiaoyong] Chongqing Univ, Sch Pharmaceut Sci, Chongqing Key Lab Nat Prod Synth & Drug Res, 55 Daxuecheng South Rd, Chongqing 401331, Peoples R China"

通信作者："Tong, XY (通讯作者)，Chongqing Univ, Sch Pharmaceut Sci, Chongqing, Peoples R China.; Tong, XY (通讯作者)，Chongqing Univ, Sch Pharmaceut Sci, Chongqing Key Lab Nat Prod Synth & Drug Res, 55 Daxuecheng South Rd, Chongqing 401331, Peoples R China."

来源：CLINICAL AND EXPERIMENTAL HYPERTENSION

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001098074700001

JCR分区：Q3

影响因子：1.5

年份：2023

卷号：45

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Pulmonary hypertension; SERCA2; pulmonary vascular remodeling; pulmonary artery smooth muscle cells; phenotypic transition; calcineurin; nuclear factor of activated T-lymphocytes

摘要："Background and Purpose: Substitution of Cys(674) (C674) in the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) causes SERCA2 dysfunction which leads to activated inositol requiring enzyme 1 alpha (IRE1 alpha) and spliced X-box binding protein 1 (XBP1s) pathway accelerating cell proliferation of pulmonary artery smooth muscle cells (PASMCs) followed by significant pulmonary vascular remodeling resembling human pulmonary hypertension. Based on this knowledge, we intend to investigate other potential mechanisms involved in SERCA2 dysfunction-induced pulmonary vascular remodeling.Experimental Approach: Heterozygous SERCA2 C674S knock-in (SKI) mice of which half of cysteine in 674 was substituted by serine to mimic the partial irreversible oxidation of C674 were used. The lungs of SKI mice and their littermate wild-type mice were collected for PASMC culture, protein expression, and pulmonary vascular remodeling analysis.Results: SERCA2 dysfunction increased intracellular Ca2+ levels, which activated Ca2+-dependent calcineurin (CaN) and promoted the nuclear translocation and protein expression of the nuclear factor of activated T-lymphocytes 4 (NFAT4) in an IRE1 alpha/XBP1s pathway-independent manner. In SKI PASMCs, the scavenge of intracellular Ca2+ by BAPTA-AM or inhibition of CaN by cyclosporin A can prevent PASMC phenotypic transition. CDN1163, a SERCA2 agonist, suppressed the activation of CaN/NFAT4 and IRE1 alpha/XBP1s pathways, reversed the protein expression of PASMC phenotypic transition markers and cell cycle-related proteins, and inhibited cell proliferation and migration when given to SKI PASMCs. Furthermore, CDN1163 ameliorated pulmonary vascular remodeling in SKI mice.Conclusions and Implications: SERCA2 dysfunction promotes PASMC phenotypic transition and pulmonary vascular remodeling by multiple mechanisms, which could be improved by SERCA2 agonist CDN1163."

基金机构："This work was supported by the National Natural Science Foundation of China (31571172 and 81870343, X.T., and 81700237, P.H.), Chongqing Natural Science Foundation (cstc2021jcyj-msxmX0043, X.T.), Special Research Assistant of the Chinese Academy of Science [31571172, 81870343, 81700237]; National Natural Science Foundation of China [cstc2021jcyj-msxmX0043]; Chongqing Natural Science Foundation; Special Research Assistant of the Chinese Academy of Sciences; Postdoctoral Research Program of Chongqing Human Resources and Social Security Bureau"

基金资助正文："This work was supported by the National Natural Science Foundation of China (31571172 and 81870343, X.T., and 81700237, P.H.), Chongqing Natural Science Foundation (cstc2021jcyj-msxmX0043, X.T.), Special Research Assistant of the Chinese Academy of Sciences (W.Y.), Postdoctoral Research Program of Chongqing Human Resources and Social Security Bureau (W.Y.)."