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Individuals with a heterozygous mutation at the ataxia-telangiectasia mutated gene (ATM) have been reported to be predisposed to ischemic heart disease. This report examined for the first time the effect of a heterozygous ATM mutation (ATM+/−) on plasma lipid levels and atherosclerosis intensity using ATM+/−, ATM+/+ (wild type), ATM+/+/LDLR−/− (low density lipoprotein receptor knockout), ATM+/−/LDLR−/−, ATM+/+/ApoE−/− (apolipoprotein E knockout), and ATM+/−/ApoE−/− mice. Our data demonstrated that the plasma cholesterol and triglyceride levels in ATM+/− and ATM+/−/LDLR−/− mice were approximately the same as those in ATM+/+ and ATM+/+/LDLR−/− control mice, respectively. In contrast, the plasma cholesterol level was significantly higher in ATM+/−/ApoE−/− mice than in ATM+/+/ApoE−/− control mice. In addition, the ATM+/−/ApoE−/− mice showed higher plasma apoB-48 levels, slower clearance for plasma apoB-48-carrying lipoproteins, and more advanced atherosclerotic lesions in the aorta compared with the ATM+/+/ApoE−/− mice.These novel results suggest that the product of ATM is involved in an apoE-independent pathway for catabolism of apoB-48-carrying remnants; therefore, superimposition of a heterozygous ATM mutation onto an ApoE deficiency background reduces the clearance of apoB-48-carrying lipoproteins from the blood circulation and promotes the formation of atherosclerosis.