SRC-3 Promotes The Development Of Atherosclerosis By Upregulating ICAM-1 Expression To Increase Monocytes Recruitment

Transcriptional coactivator steroid receptor coactivator 3(SRC-3),which belongs to a member of the p160 SRC family,can interact with multiple nuclear hormone receptors and transcription factors to regulate the expression of their target genes.Although many physiological roles of SRC-3 have been revealed,its role in atherosclerosis is not clear.Our previous study has shown that SRC-3 can promote atherosclerosis development,thus we further explored the molecular mechanism of atherosclerosis.RNA-seq and Western blot analyses of aorta revealed that SRC-3 is required for maintaining the expression of ICAM-1.ICAM-1 expressed in endothelial cells promoted atherosclerosis development,while ICAM-1 knockdown in endothelial cells alleviated atherosclerosis development,suggesting that ICAM-1 is required for atherosclerosis development.ApoE-/-mice with endothelial SRC-3 knockdown mediated by AAV9-shSRC-3 virus displayed significantly decreased macrophages content in the aortic roots and reduced WD-induced atherosclerotic plaque formation.Additionally,Pharmacological inhibition of SRC-3 reduced atherosclerosis plaque development.Furtermore,SRC-3 deficiency reduced aortic macrophages recruitment.Accordingly,ICAM-1 expression was markedly decreased in aortas of SRC-3-/-;ApoE-/-mice and ApoE-/-mice with endothelial SRC-3 knockdown mediated by AAV9-shSRC-3 virus.Mechanistically,SRC-3 coactivates p65 of NF-κB to increase ICAM-1 transcription in endothelial cells.Collectively,these findings demonstrate that inhibition of SRC-3 ameliorates atherosclerosis development,at least in part through suppressing endothelial activation by decreasing endothelial ICAM-1 expression via reducing NF-κB signaling.