Objective:To investigate the role of specificity protein 1(Sp1)/ATP-binding cassette transporter A1(ABCA1)signaling pathway in uremic atherosclerosis and its regulatory mechanism.Methods:Mouse vascular smooth muscle cells(VSMCs)were divided into control(Con)group,indophenol sulfate(IS)group,IS+Sp1 group,and IS+Sp1+sh-ABCA1 group.The Con group was treated with 0.1%DMSO for 24 h,while other groups were treated with 250 nmol/L IS for 24 h.The protein expression of Sp1/ABCA1 and lipid accumulation were analyzed by Western blot and Dil-labeled oxidized low-density lipoprotein(Dil-ox-LDL)staining.Eighty ApoE-/-mice were randomly divided into four groups:sham group,uremia accelerated atherosclerosis(UAAS)group,UAAS+Vector group,and UAAS+Sp1 group,with 20 mice in each group.Aortic lipids were measured by oil red O(ORO)staining.Results:IS promoted the fluorescence intensity of intracellular DiI-ox-LDL in a concentration-dependent manner(P<0.05).Compared with the IS group,the IS+Sp1 group had a significantly decreased fluorescence intensity of DiI-ox-LDL(P<0.01).The fluorescence intensity of DiI-ox-LDL in the IS+Sp1+sh-ABCA1 group was significantly higher than that in the IS+Sp1 group(P<0.05).Compared with the Sham group,the UAAS and UAAS+Vector groups had significantly increased ORO-positive areas in the aorta and aortic root and arch(P<0.05)and sig-nificantly reduced colocation levels of alpha-smooth muscle actin(α-SMA)and Sp1 in the aortic sinus tissue(P<0.05).Compared with the UAAS+Vector group,the UAAS+Sp1 group had signifi-cantly reduced ORO-positive areas in the aorta and aortic root and arch(P<0.05)and significantly increased colocation levels of α-SMA and Sp1(P<0.05).The protein expression levels of Sp1 and ABCA1 in the aortic tissue of the UAAS+Sp1 group were significantly higher than those of the UAAS+Vector group(P<0.05).Conclusion:Uremic toxin IS may induce lipid accumulation in the VSMCs by inhibiting the Sp1/ABCA1 signaling pathway,thus accel-erating endothelial dysfunction in uremia and promoting the progression of atherosclerosis.