Atorvastatin Promotes Autophagy Of Vascular Smooth Muscle Cells To Delay The Progression Of Atherosclerosis Via AMPK/mTOR Pathway

Background and purpose:Atherosclerosis is an important factor for ischemic stroke and coronary heart disease.Studies have shown that autophagy can delay the progression of atherosclerosis by promoting lipid efflux from foam cells.In addition to lowering cholesterol,atorvastatin also has pleiotropic effects such as reducing systemic inflammatory response,stabilizing plaque,improving vascular endothelial function and reducing platelet hyperresponsiveness.Whether atorvastatin can affect the lipid flux of foam cells by promoting autophagy is not clear.The aim of this study was to investigate whether atorvastatin can promote the progression of atherosclerosis by autophagy promoting lipid efflux from smooth muscle cells.Methods:8-week-old male apoe^-/-mice?C57BL/6?were fed a high-fat diet for 8weeks,and then administered to the blank control and atorvastatin?10 mg/kg?by means of jelly administration.After 4 weeks,they were executed.We examined the changes in plaque size,stability at the aortic as also as the changes in VSMCs-derived foam cells at the heart valve.In cell experiments,we used ox-LDL to induce VSMCs foaming.Then,we detected changes in lipid efflux rate,cholesterol ester,the phosphorylation level of key autophagy molecule mTORC1/ULK1,autophagy progression marker LC3 and the expression level of the LC3 substrate P62 after atorvastatin treatment.Finally,we detected changes in the expression of the above autophagy-related molecules after the addition of the AMPK inhibitor Compound C.Results:1.Compared with the control,the atorvastatin group had less atherosclerotic plaque in the aorta and heart valve,reduced necrotic core,increased plaque stability,and immunofluorescence showed smooth muscle cell-derived foam cells are reduced.2.The results of cell experiments showed that the lipid efflux rate of foamed vascular smooth muscle cells increased after atorvastatin administration,and the content of cholesterol ester in cells decreased.3.This study also found that the p-mTOR and the p-ULK1-Ser757 decreased,the expression level of autophagy progression marker LC3 increased,the expression level of P62 was decreased after atorvastatin administration;meanwhile,the phosphorylation level of AMPK was increased in the upstream of autophagy pathway.The expression level of LC3 was decreased after Compound C was administered,the expression level of P62 was increased,the rate of lipid efflux was decreased,and the content of cholesterol ester was increased.It is true that atorvastatin promotes the increase of lipid efflux by autophagy of smooth muscle cells by promoting phosphorylation of AMPK.4.After administration of the autophagy inhibitor chloroquine,the effect of atorvastatin on autophagy was inhibited,further confirming the effect of atorvastatin on vascular smooth muscle cells.Conclusion:Atorvastatin can delay the progression of atherosclerosis by autophagy of vascular smooth muscle cells through AMPK/mTOR/ULK1 pathway?...