Sterol-resistant SCAP Overexpression in Vascular Smooth Muscle Cells Accelerates Atherosclerosis by Increasing Local Vascular Inflammation through Activation of the NLRP3 Inflammasome in Mice

作者全名："Li, Danyang; Liu, Mihua; Li, Zhe; Zheng, Guo; Chen, Amei; Zhao, Lei; Yang, Ping; Wei, Li; Chen, Yaxi; Ruan, Xiong Z."

作者地址："[Li, Danyang; Liu, Mihua; Li, Zhe; Zheng, Guo; Chen, Amei; Zhao, Lei; Yang, Ping; Wei, Li; Chen, Yaxi; Ruan, Xiong Z.] Chongqing Med Univ, Ctr Lipid Res, Affiliated Hosp 2, Chongqing, Peoples R China; [Li, Danyang; Liu, Mihua; Li, Zhe; Zheng, Guo; Chen, Amei; Zhao, Lei; Yang, Ping; Wei, Li; Chen, Yaxi; Ruan, Xiong Z.] Chongqing Med Univ, Key Lab Mol Biol Infect Dis, Minist Educ, Inst Viral Hepatitis,Dept Infect Dis,Affiliated H, Chongqing, Peoples R China; [Ruan, Xiong Z.] Fudan Univ, Huashan Hosp, Natl Clin Res Ctr Aging & Med, Shanghai, Peoples R China; [Ruan, Xiong Z.] UCL, Med Sch, Ctr Nephrol, John Moorhead Res Lab, Royal Free Campus, London, England"

通信作者："Chen, YX; Ruan, XZ (corresponding author), Chongqing Med Univ, Affiliated Hosp 2, Chongqing, Peoples R China."

来源：AGING AND DISEASE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000667454200009

JCR分区：Q1

影响因子：7.4

年份：2021

卷号：12

期号：3

开始页：747

结束页：763

文献类型：Article

关键词：SCAP; Inflammation; Atherosclerosis; VSMC; NLRP3

摘要："Atherosclerosis is a serious age-related pathology, and one of its hallmarks is the presence of chronic inflammation. Sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) is a cholesterol sensor that plays an essential role in regulating intracellular cholesterol homeostasis. Accordingly, dysregulation of the SCAP-SREBP pathway has been reported to be closely associated with an increased risk of obesity, hypercholesterolemia, and cardiovascular disease. In this study, we explored whether sterol-resistant SCAP (D443N mutation) in vascular smooth muscle cells (VSMCs) of mice promotes vascular inflammation and accelerates the occurrence and progression of atherosclerosis. We established a transgenic knock-in mouse model of atherosclerosis with an activating D443N mutation at the sterol-sensing domain of SCAP (SCAP(D443N)) by microinjection. Next, SCAP(D443N)/ApoE(-/-) mice were generated by crossing SCAP(D443N) mice with apolipoprotein E-/- (ApoE(-/-)) background mice. We found that sterol-resistant SCAP markedly amplified and accelerated the progression of atherosclerotic plaques in SCAP(D443N)/ApoE(-/-) mice compared with that in control ApoE(-/-) mice. Similarly, in SCAP(D443N) mice, aortic atherosclerotic plaques both appeared earlier and were greater in number than that in control SCAP(+/+) mice, both of which were fed a Western diet for 12 or 24 weeks. Moreover, we observed that sterol-resistant SCAP significantly increased local inflammation and induced endothelial dysfunction in the aortas of SCAP(D443N) mice and SCAP(D443N)/ApoE(-/-) mice. In vitro, we also found that sterol-resistant SCAP overexpression in VSMCs increased the release of inflammatory cytokines and induced endothelial cell injury when both cell types were cocultured. Furthermore, we demonstrated that sterol-resistant SCAP overexpression in VSMCs promoted SCAP and NLRP3 inflammasome cotranslocation to the Golgi and increased the activation of the NLRP3 inflammasome pathway. These findings suggested that sterol-resistant SCAP in VSMCs of mice induced vascular inflammation and endothelial dysfunction, consequently accelerating atherosclerosis by activating the NLRP3 inflammasome pathway."

基金机构："National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81873569, 81900406, 32030054]; National Key R&D Program of China [2018YFC1312700]; Science and Technology Research Program of Chongqing Municipal Education Commission [KJZD-K201800401]; Chongqing Research Program of Basic Research and Frontier Technology [cstc2020jcyj-zdxmX0007]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2019M663448]; Natural Science Foundation of Chongqing ProvinceNatural Science Foundation of Chongqing [CSTC2019JCYJBSHX0094]; 111 ProjectMinistry of Education, China - 111 Project [D20028]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (81873569, 81900406, Key Program, No. 32030054); National Key R&D Program of China (2018YFC1312700); the Science and Technology Research Program of Chongqing Municipal Education Commission (Grant No. KJZD-K201800401); the Chongqing Research Program of Basic Research and Frontier Technology (cstc2020jcyj-zdxmX0007); the China Postdoctoral Science Foundation (Grant No.2019M663448); the Natural Science Foundation of Chongqing Province (Grant No.CSTC2019JCYJBSHX0094); and the 111 Project (No. D20028)."