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

Danyang Li; Mihua Liu; Zhe Li; Guo Zheng; Amei Chen; Lei Zhao; Ping Yang; Li Wei; Yaxi Chen; Xiong Z Ruan

doi:10.14336/AD.2020.1120

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

Aging Dis. 2021 Jun 1;12(3):747-763. doi: 10.14336/AD.2020.1120. eCollection 2021 Jun.

Authors

Danyang Li¹, Mihua Liu¹, Zhe Li¹, Guo Zheng¹, Amei Chen¹, Lei Zhao¹, Ping Yang¹, Li Wei¹, Yaxi Chen¹, Xiong Z Ruan^{1

2

3}

Affiliations

¹ 1Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
² 2National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
³ 3John Moorhead Research Laboratory, Centre for Nephrology, University College London Medical School, Royal Free Campus, University College London, London, United Kingdom.

Abstract

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.

Keywords: Atherosclerosis; Inflammation; NLRP3; SCAP; VSMC.