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 (SCAPD443N) by microinjection. Next, SCAPD443N/ApoE-/- mice were generated by crossing SCAPD443N mice with apolipoprotein E-/- (ApoE-/-) background mice. We found that sterol-resistant SCAP markedly amplified and accelerated the progression of atherosclerotic plaques in SCAPD443N/ApoE-/- mice compared with that in control ApoE-/- mice. Similarly, in SCAPD443N 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 SCAPD443N mice and SCAPD443N/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.

Highlights

  • Atherosclerosis is a serious age-related pathology, and one of its hallmarks is the presence of chronic inflammation

  • We generated a new mouse model of sterol-resistant SCAP (D443N mutation) in vascular smooth muscle cells (VSMCs) crossed with the hyperlipidemic ApoE-/- mouse to elucidate the mechanisms linking cholesterol metabolism and inflammatory disorders in the development of atherosclerosis

  • Overexpression of sterol-resistant SCAP in VSMCs leads to an increase in atherosclerotic plaque formation independent of serum cholesterol levels; intriguingly, SCAPD443N mice display hallmarks of fatty streak lesions characterized by loss of endothelial cell function and accelerated early atherogenesis

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Summary

Introduction

Atherosclerosis is a serious age-related pathology, and one of its hallmarks is the presence of chronic inflammation. 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, accelerating atherosclerosis by activating the NLRP3 inflammasome pathway. Sterol-resistant SCAP (D443N) causes insensitivity to sterol and facilitates SCAP-SREBP complex translocation from the ER to the Golgi and proteolytic processing of native SREBPs in the Golgi, even in the presence of sterols [18, 19] These mutations indicated that increased SCAP signaling would promote hypercholesterolemia, the role of sterol-resistant SCAP in atherosclerosis has not been studied. To elucidate the mechanisms of sterol-resistant SCAP in the development of atherosclerosis, it is crucial to generate an improved mouse model of atherosclerosis with an activating D443N mutation in SCAP

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