Ezetimibe-Mediated Protection of Vascular Smooth Muscle Cells from Cholesterol Accumulation through the Regulation of Lipid Metabolism-Related Gene Expression

Abstract

Background: Ezetimibe is a potent inhibitor of Niemann-Pick type C1-Like 1 and has been approved for the treatment of hypercholesterolemia. Our preliminary study showed that ezetimibe promotes cholesterol efflux from vascular smooth muscle cells (VSMCs). Our aim was to investigate the cellular mechanisms underlying the ezetimibe actions. Methods and Results: Rat VSMCs were converted to foam cells by incubation with cholesterol:methyl-F-cyclodextrin. The intracellular free cholesterol, total cholesterol, and the ratio of cholesteryl ester to total cholesterol were decreased after the incubation of VSMCs with different concentrations of ezetimibe (3, 10, 30, and 30 Vmol/l) or treated with 30 Vmol/l of ezetimibe for different time periods (6, 12, 24, and 48 h). Our results also showed that the expression of caveolin-1, liver X receptor E, and ATP-binding cassette transporter ABCA1 was enhanced, but the expression of nSREBP-1c was decreased in a concentration- and time-dependent manner. RNA interference was used to determine the roles of caveolin-1 and SREBP-1 in the lipid-lowering effect of ezetimibe. The results showed that caveolin-1 was involved in the regulation of intracellular cholesterol content, and the expression of caveolin-1 was repressed by SREBP-1. Conclusion: The present study indicates that ezetimibe protects VSMCs from cholesterol accumulation by regulating the expression of lipid metabolism-related genes. i 2014 S. Karger AG, Basel

Caveolin-1 Alleviates Acetaminophen-Induced Fat Accumulation in Non-Alcoholic Fatty Liver Disease by Enhancing Hepatic Antioxidant Ability via Activating AMPK Pathway

“…It was reported that sterol regulatory element binding proteins (SREBPs) expression was mainly regulated by cellular cholesterol and CAV1 was negatively regulated by SREBPs ( Xu et al, 2010 ; Fernandez-Rojo and Ramm, 2016 ). Besides, several studies have suggested that there is a molecular loop of reciprocal control between liver CAV1 and lipid metabolism ( Gong et al, 2014 ; Fernandez-Rojo and Ramm, 2016 ). Therefore, the decreased CAV1 level after inhibiting AMPK activation may be the consequence of abnormal lipid metabolism and increased SREBPs protein expression in cells.…”

Caveolin-1 Expression Ameliorates Nephrotic Damage in a Rabbit Model of Cholesterol-Induced Hypercholesterolemia

“…CAV-1 may mediate cellular cholesterol efflux to high-density lipoprotein (HDL) [ 4 , 5 ]. Several studies have revealed that CAV-1 protein overexpression markedly reduced total cholesterol and free cholesterol (FC) content as well as their accumulation in lipid-loading cells [ 6 – 8 ]. In CAV-1-deficient mice, moderately elevated whole-lung cholesterol content, impaired liver regeneration, cardiovascular disorders, and FC accumulation in mitochondrial membranes resulted in mitochondrial diseases [ 9 – 11 ].…”