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The elevated homocysteine level is an independent risk factor for atherosclerosis,which is charac-terized as a chronic inflammatory disease associated with oxidative stress.We have confirmed that homocysteine can stimulate the production of C-reactive protein(CRP)in rat aortic smooth muscle cells(RASMCs).In the present study,we investigated the role of probucol in homocysteine-induced CRP expression in cultured RASMCs and high-methionine-diet-induced hyperhomocysteinemic rats.The results showed that probucol decreased homocysteine-induced CRP mRNA and protein expression in RASMCs in a concentration-dependent manner.In addition,the animal experiment showed that probucol not only inhibited CRP expression in the vessel wall but also reduced the circulating CRP level in hyperhomocysteinemic rats.Further investigations revealed that probu-col markedly increased heme oxygenase-1 activity,suppressed nicotinamide adenine dinucleotide phosphate(NADPH)oxidase activity,diminished superoxide anion generation,and decreased p38 phosphorylation in RASMCs and hyperhomocysteinemic rat aorta.These data demonstrate that probucol can inhibit homocysteine-induced CRP generation by interfering with the NADPH oxi-dase/p38 signal pathway in RASMCs,which will provide new evidence for the anti-inflammatory and anti-atherosclerotic effects of probucol.