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Objective-Destruction of the elastic media is the most striking histologic feature of atherosclerotic aortic aneurysms.Apolipoprotein E-deficient (apoE -/-) mice fed a Western diet develop advanced atherosclerotic lesions in the aorta. We sought to assess the integrity of atherosclerotic aortic walls in 2 apoE -/-strains, C57BL/6 (B6) and C3H/HeJ (C3H) that differ markedly in atherosclerosis susceptibility. Methods and Results-C3H.apoE-/-mice developed much smaller atherosclerotic lesions than did B6.apoE -/-mice after being fed a Western diet for 16 weeks, but the C3H.apoE Ϫ/Ϫ mice exhibited destruction of the elastic media, including erosion, fragmentation, and focal dilatation beneath plaques. Gelatin and casein zymography showed proteolytic activity of matrix metalloproteinases (MMPs) -9, -2, and -12 in aortic tissues and of MMP-9 and -12 in macrophages from both strains. However, C3H.apoE -/-mice showed significantly increased MMP-2 and -12 activity in aortas and macrophages compared with those from B6.apoE -/-mice. MMP-9 activity was comparable in aortic tissues of the 2 strains, but it was significantly higher in macrophages from C3H.apoE -/-than from B6.apoE -/-mice. Conclusions-Data indicate that genetic backgrounds but not sizes of atherosclerotic lesions determine medial destruction in the aortic root of apoE -/-mice and that an increase in MMP proteolytic activity might contribute to the medial destruction of aortic walls in C3H.apoE

LDL deposition in the subendothelium of arterial walls is the initial event in the development of atherosclerosis. The deposited LDL undergoes oxidative modification by arterial wall cells to become oxidized LDL and consequently contributes to atherosclerotic formation. Using mouse strains C57BL/6J (B6) and C3H/HeJ (C3H), which differ markedly in susceptibility to atherosclerosis, we determined whether variation in subendothelial retention of apolipoprotein B (apoB)-containing lipoproteins constitutes a genetic component in atherosclerosis. Lipoprotein retention was quantitated by Western blot analysis to detect the presence of apoB in aortic walls before foam cells developed. In both dietary and apoE-deficient models, B6 mice exhibited up to a 2-fold increase of apoB in the aortic wall compared with C3H mice. This increase could not be attributed to differences in plasma lipid levels of the two strains. In vitro, endothelial cells from C3H mice took up more acetylated and oxidized LDL but not native LDL and converted more native LDL to oxidized LDL than did endothelial cells from B6 mice. C3H mice expressed more scavenger receptor A in their aortic wall than B6 mice. Thus, variation in the subendothelial retention of apoB-containing lipoproteins cannot explain the dramatic difference in atherosclerosis susceptibility between B6 and C3H mice, and endothelial cells may play a role in alleviating lipid accumulation in arterial walls. -Brown, M.

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