SRC-3 deficiency prevents atherosclerosis development by decreasing endothelial ICAM-1 expression to attenuate macrophage recruitment

Steroid receptor coactivator 3 (SRC-3) is a member of the p160 SRC family.This factor 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.In this study, we found that SRC-3 -/-ApoE -/-mice have reduced atherosclerotic lesions and necrotic areas in their aortas and aortic roots compared with SRC-3 +/+ ApoE -/-mice after Western diet (WD) feeding for 12 weeks.RNA-Seq and Western blot analyses of the aorta revealed that SRC-3 was required for maintaining the expression of ICAM-1, which was required for macrophage recruitment and atherosclerosis development.siRNA-mediated knockdown of SRC-3 in endothelial cells significantly reduced WD-induced atherosclerotic plaque formation.Additionally, treatment of ApoE -/-mice with SRC-3 inhibitor bufalin prevented atherosclerotic plaque development.SRC-3 deficiency reduced aortic macrophage recruitment.Accordingly, ICAM-1 expression was markedly decreased in the aortas of SRC-3 -/-ApoE -/-mice and ApoE -/-mice with endothelial SRC-3 knockdown mediated by AAV9-shSRC-3 virus.Mechanistically, SRC-3 coactivated NF-κB p65 to increase ICAM-1 transcription in endothelial cells.Collectively, these findings demonstrate that inhibiting SRC-3 ameliorates atherosclerosis development, at least in part through suppressing endothelial activation by decreasing endothelial ICAM-1 expression via reducing NF-κB signaling.