P250	Increased atherosclerotic burden in young versus aged LDLr-/- mice.
1A.Kraaijeveld, 1R.de Nooijer, 2B.Meijboom, 1E.van der Wall, 1W.Jukema, 2T.van Berkel, 2E.Biessen
1Leiden University Medical Centre, Deparment of Cardiology, Leiden, NL; 2Leiden University, LACDR, Division of Biopharmaceutics, Leiden, NL.

Objective: Aging is regarded as a major risk factor in the development of atherosclerosis. However, it is still unclear whether it directly or indirectly impacts the process of atherogenesis. This study focuses on the effect of aging in de novo collar induced atherosclerosis in LDLr-/- mice with emphasis on lesion size, morphology and vascular remodeling. Methods and results: Atherosclerotic lesions were elicited in carotid arteries of young (12 weeks, n=16) and aged (52 weeks, n=15) LDLr-/- mice by bilateral perivascular collar placement after six weeks of Western type diet. Throughout the experiment, cholesterol levels were found to be consistently increased in young vs. aged mice (baseline sample 1690 vs. 1294 mg/dl; P<0.001). PCR analysis on liver for cholesterol metabolism related genes revealed a lower FXR (P=0.03) and Cyp7α (P=0.04) expression in old mice. Six weeks after surgery, carotid and brachiocephalic arteries as well as aortic roots were harvested and analyzed histologically. Carotid plaque (40,500 vs. 14,800 μm2, P<0.04) and media size (52,300 vs. 33,600 μm2, P<0.02) were larger in young vs. aged mice. Intriguingly, due to a substantial outward remodeling in younger mice (total vessel area 179,400 vs. 113,500 μm2, P<0.04), their lumen areas were even increased as compared to their aged counterparts (86,572 vs. 65,122 μm2, P<0.04). In line with this finding, aortic root plaque size was larger in young mice (7,38x105 vs. 5,06x105 μm2, P<0.03) as well, the brachiocephalic artery plaques of both age groups displayed the same tendency. Focusing at plaque composition, collagen and macrophage content were comparable in plaques from both age groups, suggesting that age per se is not a causal factor in plaque stability. Micro array analysis of carotid arteries from both groups identified 2 specific genes, TGFβ-3 and QkI, which could be involved in the hampered remodeling response upon aging. Conclusions: Reduced plasma cholesterol levels, decreased atherogenesis and outward remodeling accompany increasing age in our model. Thus, while the atherogenic propensity may even be quenched at high age, the loss of remodeling capacity of aged vessels leading to loss of lumen may aggravate the clinical repercussion of atherosclerosis considerably.

Copyright © 2005 S. Karger AG, Basel. Any further use of this abstract requires written permission from the publisher.