Effect of aging on aortic expression of the vascular cell adhesion molecule-1 and atherosclerosis in murine models of atherosclerosis.

Although age is a strong risk factor for atherosclerosis, it is unclear whether age may directly influence the process of atherogenesis. We, therefore, performed several studies in young (2-4 months old), mature (10-14 months old), and old (20-22 months old) mice to determine if the rate of aortic lesion formation increases with age, and whether this is related to increases in oxidative stress or vascular cell adhesion molecule (VCAM-1) expression in the aortic wall. In chow-fed low-density lipoprotein receptor-deficient (LDLR-/-) mice, plasma total cholesterol levels increased with age (250 +/- 52 mg/dl in young, 276 +/- 58 in mature, and 314 +/- 101 mg/dl in old mice). In contrast, the extent of atherosclerosis rose more rapidly, increasing from 3.6 +/- 2.7% of the aortic surface in mature mice to 18.2 +/- 8% in old mice. Plasma and tissue levels of antioxidant enzymes and molecules, as well as plasma thiobarbituric acid reactive substances and low-density lipoprotein susceptibility to oxidation, did not change with age. In a second study, VCAM-1 expression in the aortic arch and the extent of atherosclerosis in the aortic origin were significantly greater in old LDLR-/- mice than in young LDLR-/- mice. Additionally, after 1 month of a high-fat diet, which induced equally elevated plasma cholesterol levels in both young and old LDLR-/- mice, VCAM-1 expression and aortic lesion formation were still greater in old mice. The extent of atherosclerosis correlated well (r = .65,p <.01) with the expression of VCAM-1 in the aortic origin. In a final study, we measured VCAM-1 expression and atherosclerosis in young, mature, and old C57BL/6 mice, which have low plasma cholesterol levels (< or =100 mg/dl) when fed a standard chow diet. Although plasma cholesterol levels did not increase with age, old C57BL/6 mice had significantly more VCAM-1 expression in the aortic arch than did young mice. However, no lesions were observed in the aortic origin in either group. These data demonstrate that plasma cholesterol levels and VCAM-1 expression increase with age and suggest that this may contribute to the increased rate of atherosclerotic lesion formation in LDLR-/- mice. Importantly, the age-dependent increase in VCAM-1 expression does not appear to be related to plasma cholesterol levels. This study also suggests that in the absence of elevated plasma cholesterol, an increased expression of VCAM-1 alone is not sufficient for lesion formation.