Journals of Gerontology Series A: Biological Sciences and Medical Sciences, Vol 55, Issue 2 B85-B94, Copyright © 2000 by The Gerontological Society of America
Effect of aging on aortic expression of the vascular cell adhesion molecule-1 and atherosclerosis in murine models of atherosclerosis
S Merat, J Fruebis, M Sutphin, M Silvestre and PD Reaven
Department of Medicine, University of California San Diego, La Jolla, USA.
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.
