Genetic reduction of lipoic acid synthase expression modestly increases atherosclerosis in male, but not in female, apolipoprotein E-deficient mice.

OBJECTIVES:To evaluate the effects of a genetic reduction of Lias gene expression on atherosclerosis development. METHODS AND RESULTS:Heterozygous knockout mice for the lipoid acid synthase gene (Lias(+/-)) were crossed with apolipoprotein E-deficient (ApoE(-/-)) mice, and the plaque size in aortic sinuses of Lias(+/-)ApoE(-/-)mice was evaluated at 6 months of age. Lesions at the aortic sinus in Lias(+/-)ApoE(-/-) males were significantly larger (1.5x) than those in Lias(+/+) ApoE(-/-) littermate males. The lesion size was inversely correlated with an increased erythrocyte reduced glutathione/oxidized glutathione (GSH/GSSH) ratio, a systemic index of body redox balance. Lias(+/-)ApoE(-/-)males also had significantly increased plasma cholesterol and reduced pyruvate dehydrogenase complex activity in the liver. Significant reductions in the expression of genes for antioxidant enzymes, including superoxide dismutase 1 (SOD1) and SOD2, were observed in aortas of Lias(+/-)ApoE(-/-)males. Female Lias(+/-)ApoE(-/-)also exhibited changes in these parameters, parallel to those observed in males. However, the Lias gene effects for the majority of these factors, including atherosclerotic lesion size, were not significant in females. CONCLUSIONS:Our data provide evidence that Lias deficiency enhances atherosclerosis in male mice, at least in part due to reduced antioxidant capacity. The notable absence of such effects in females leaves open the possibility of a gender-specific protection mechanism.

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