Transcriptional Coactivator SRC-3 Promotes Atherosclerosis And Study Of Mechanism

Transcriptional coactivator steriod receptor coactivator 3(SRC-3)is a member of the p160 SRC family.It can interact with multiple nuclear receptors and transcription factors to enhance their target genes expression.Athough many physiological and pathological roles of SRC-3 have been studied,its role in atherosclerosis is not clear.Atherosclerosis is a chronic disease of the large arteries which is the marjor cause of stroke and myocardial infarction.Recently,we found that SRC-3 is highly expressed in the vascular smooth muscle cells and endothelial cells of aortic roots in SRC-3+/-ApoE-/-mice and upregulated after being fed a hight fat(HF)diet for 12 weeks,suggesting that SRC-3 may be involved in atherosclerosis.In this study,we studied the role of SRC-3 in atherosclerosis by comparing the atherosclerotic lesions of SRC-3-/-ApoE-/-mice and SRC-3+/+ApoE-/-mice after being fed a HF diet for 12 weeks.We found that SRC-3-/-ApoE-/-mice displayed less atherosclerotic lesions and necrotic area in the aortas and aortic roots compared to SRC-3+/+ApoE-/-mice after being fed a HF diet for 12 weeks.what's more,fibrous cap thickness and collagen content of aortic root in SRC-3-/-ApoE-/-mice were markedly increased than those in SRC-3+/+ApoE-/-mice.Although the number of endothiel cells,neutrophils and CD4+T cells in aortic root lesions were similar between SRC-3-/-ApoE-/-mice and SRC-3+/+ApoE-/-mice after being fed a HF diet for 12 weeks,macrophages and vascular smooth muscle cells of aortic root lesions were reduced in 12 weeks HF fed SRC-3-/-ApoE-/-mice compared with SRC-3+/+ApoE-/-mice.And we found that the expression of ICAM-1,VCAM-1 in the aortic root lesion and proinflammatory cytokines IL-6 and IL-1? in the plasma were significantly decreased in 12 weeks HF fed SRC-3-/-ApoE-/-mice.In addition,the ability of forming foam cells of peritoneal macrophages from SRC-3-/-ApoE-/-mice was notably attenuated compare that from SRC-3+/+ApoE-/-mice and knock-down SRC-3 can reduce CD36 expression in RAW264.7 cells.Furthermore,triglyceride content in the plasma and liver of 12 weeks HF fed SRC-3-/-ApoE-/-mice was decreased and SRC-3 deficience reduced CD36 expression in the liver.At transcriptional level,we found that SRC-3 can cooperate AP-1 to promote CD36 expression.Additionally,SRC-3 was frequently overexpressed in human AS tissues.Furthermore,SRC-3 inhibitor bufalin ameliorated atherosclerosis.Collectively,we demonstrate that SRC-3 can promote atherosclerosis by promoting inflammotary response,increasing macrophages infiltration and foam cells formation to accelerate foam cells formation and accumulate triglyceride.