Reduced alpha-lipoic acid synthase gene expression exacerbates atherosclerosis in diabetic apolipoprotein E-deficient mice.
OBJECTIVE
To study the effects of reduced lipoic acid gene expression on diabetic atherosclerosis in apolipoprotein E null mice (Apoe(-/-)).


RESULTS
Heterozygous lipoic acid synthase gene knockout mice (Lias(+/-)) crossed with Apoe(-/-) mice were used to evaluate the diabetic effect induced by streptozotocin on atherosclerosis in the aortic sinus of the heart. While diabetes markedly increased atherosclerotic plaque size in Apoe(-/-) mice, a small but significant effect of reduced expression of lipoic acid gene was observed in diabetic Lias(+/-)Apoe(-/-) mice. In the aortic lesion area, the Lias(+/-)Apoe(-/-) mice exhibited significantly increased macrophage accumulation and cellular apoptosis than diabetic Lias(+/+)Apoe(-/-) littermates. Plasma glucose, cholesterol, and interleukin-6 were also higher. These abnormalities were accompanied with increased oxidative stress including a decreased ratio of reduced glutathione/oxidized glutathione in erythrocytes, increased systemic lipid peroxidation, and increased Gpx1 and MCP1 gene expression in the aorta.


CONCLUSIONS
Decreased endogenous lipoic acid gene expression plays a role in development of diabetic atherosclerosis. These findings extend our understanding of the role of antioxidant in diabetic atherosclerosis.
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 27599-7525, USA. xyi2000@med.unc.edu
Xianwen
X
Yi
Longquan
L
Xu
Sylvia
S
Hiller
Hyung-Suk
HS
Kim
Nobuyo
N
Maeda
D000818:Animals; D001018:Aortic Diseases / Q000097:blood / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D017209:Apoptosis; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D001786:Blood Glucose / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005978:Glutathione / Q000097:blood; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D018384:Oxidative Stress; D012850:Sinus of Valsalva / Q000201:enzymology* / Q000473:pathology; D013466:Sulfurtransferases / Q000172:deficiency* / Q000235:genetics; D000094765:Glutathione Peroxidase GPX1
D001057:Apolipoproteins E; D001786:Blood Glucose; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D015850:Interleukin-6; D002784:Cholesterol; D005979:Glutathione Peroxidase; D013466:Sulfurtransferases; C116435:lipoic acid synthase; D005978:Glutathione; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse