Inhibition of VCAM-1 expression in the arterial wall is shared by structurally different antioxidants that reduce early atherosclerosis in NZW rabbits

We previously established that probucol decreases basaI expression of VCAM- 1 in the aorta of WHHL rabbits and inhibits the up-regulation of VCAM-1 exp ression that normally accompanies atherogenesis, To determine whether this- effect is shared by other antioxidants in vivo, we now investigated whether a structurally unrelated antioxidant, vitamin E,also inhibits arterial VCA M-1 expression and whether the degree of VCAM-1 inhibition correlates with the reduction of atherosclerosis or the antioxidant protection of LDL, Athe rogenesis and VCAM-1 mRNA and protein were determined in four groups of NZW rabbits (n = 6-8) fed 0.5%- cholesterol alone or supplemented with 0.1% vi tamin E, a low dose (0.04-0.075%) of probucol yielding the same degree of a ntioxidant protection of plasma LDL as vitamin E, or a high dose (0.5%) of probucol, and in normocholesterolemic rabbits. After 81 days, extensive ath erosclerosis and a greater than 4-fold up-regulation of VCAM-1 mRNA was see n in rabbits on high cholesterol diet, mostly in the intima, Treatment with vitamin E, high-dose probucol, and low-dose probucol significantly decreas ed VCAM-1 mRNA by 49.0, 74.9, and 57.5%, respectively, and reduced atherosc lerosis in adjacent segments of the thoracic aorta to a similar degree as r eported by previous studies, Immunocytochemistry confirmed that lesions of antioxidant-treated animals also contained less VCAM-1 protein, Neither the degree of VCAM-1 inhibition nor the extent of atherosclerosis correlated w ith the degree of antioxidant protection of plasma LDL. In summary, treatme nt with structurally unrelated antioxidants conveyed different degrees of a ntioxidant protection to plasma LDL but significantly reduced VCAM-1 expres sion in vivo and inhibited atherogenesis, This is consistent with the assum ption that antiatherogenic effects of antioxidants may in part be mediated by interference with oxidation-dependent intracellular signaling:-Fruebis, J., M. Silvestre, D. Shelton, C. Napoli, and W. Palinski. Inhibition of VCA M-1 expression in the arterial wall is shared by structurally different ant ioxidants that reduce early atherosclerosis in NZW rabbits.