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(Circulation. 2008;117:421-428.)
© 2008 American Heart Association, Inc.

Vascular Medicine

Dietary -Lipoic Acid Supplementation Inhibits Atherosclerotic Lesion Development in Apolipoprotein E–Deficient and Apolipoprotein E/Low-Density Lipoprotein Receptor–Deficient Mice

Wei-Jian Zhang, MD, PhD; Karyn E. Bird, DVM, PhD; Timothy S. McMillen, PhD; Renee C. LeBoeuf, PhD; Tory M. Hagen, PhD; Balz Frei, PhD

From the Linus Pauling Institute (W.-J.Z., T.M.H., B.F.) and Department of Biomedical Sciences, College of Veterinary Medicine (K.E.B.), Oregon State University, Corvallis, and Division of Metabolism, Endocrinology, and Nutrition (T.S.M., R.C.L.), Department of Medicine, University of Washington, Seattle.

Correspondence to Wei-Jian Zhang, MD, PhD, or Balz Frei, PhD, Linus Pauling Institute, Oregon State University, 571 Weniger Hall, Corvallis, OR 97331. E-mail weijian.zhang{at}oregonstate.edu or balz.frei@oregonstate.edu

Received October 11, 2006; accepted October 31, 2007.

Background— Vascular inflammation and lipid deposition are prominent features of atherosclerotic lesion formation. We have shown previously that the dithiol compound -lipoic acid (LA) exerts antiinflammatory effects by inhibiting tumor necrosis factor-– and lipopolysaccharide-induced endothelial and monocyte activation in vitro and lipopolysaccharide-induced acute inflammatory responses in vivo. Here, we investigated whether LA inhibits atherosclerosis in apolipoprotein E–deficient (apoE^–/–) and apoE/low-density lipoprotein receptor–deficient mice, 2 well-established animal models of human atherosclerosis.

Methods and Results— Four-week–old female apoE^–/– mice (n=20 per group) or apoE/low-density lipoprotein receptor–deficient mice (n=21 per group) were fed for 10 weeks a Western-type chow diet containing 15% fat and 0.125% cholesterol without or with 0.2% (wt/wt) R,S-LA or a normal chow diet containing 4% fat without or with 0.2% (wt/wt) R-LA, respectively. Supplementation with LA significantly reduced atherosclerotic lesion formation in the aortic sinus of both mouse models by 20% and in the aortic arch and thoracic aorta of apoE^–/– and apoE/low-density lipoprotein receptor–deficient mice by 55% and 40%, respectively. This strong antiatherogenic effect of LA was associated with almost 40% less body weight gain and lower serum and very low-density lipoprotein levels of triglycerides but not cholesterol. In addition, LA supplementation reduced aortic expression of adhesion molecules and proinflammatory cytokines and aortic macrophage accumulation. These antiinflammatory effects of LA were more pronounced in the aortic arch and the thoracic aorta than in the aortic sinus, reflecting the corresponding reductions in atherosclerosis.

Conclusions— Our study shows that dietary LA supplementation inhibits atherosclerotic lesion formation in 2 mouse models of human atherosclerosis, an inhibition that appears to be due to the "antiobesity," antihypertriglyceridemic, and antiinflammatory effects of LA. LA may be a useful adjunct in the prevention and treatment of atherosclerotic vascular diseases.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2008 117: 331-332. [Full Text]