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on October 13, 2005

Arteriosclerosis, Thrombosis, and Vascular Biology. 2005
Published online before print October 13, 2005, doi: 10.1161/01.ATV.0000190667.33224.4c
A more recent version of this article appeared on December 1, 2005
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Submitted on March 7, 2005
Accepted on September 7, 2005

{alpha}-Lipoic Acid Prevents Endothelial Dysfunction in Obese Rats via Activation of AMP-Activated Protein Kinase

Woo Je Lee ; In Kyu Lee ; Hyoun Sik Kim ; Yun Mi Kim ; Eun Hee Koh ; Jong Chul Won ; Sung Min Han ; Min-Seon Kim ; Inho Jo ; Goo Taeg Oh ; In-Sun Park ; Jang Hyun Youn ; Seong-Wook Park ; Ki-Up Lee ; and Joong-Yeol Park *

From the Department of Internal Medicine (W.J.L, E.H.K., J.C.W., S.M.H., M.-S.K., S.W.P., K.-U.L., J.-Y.P.), Asan Institute for Life Sciences (H.S.K., Y.M.K.), University of Ulsan College of Medicine, Seoul, Republic of Korea; the Department of Internal Medicine (I.K.L.), Kyungpook National University School of Medicine, Daegu, Republic of Korea; the Division of Cardiovascular Research (I.J.), Korean National Institute of Health, Seoul, Republic of Korea; the Laboratory of Cardiovascular Genomics (G.T.O.), Division of Molecular Life Sciences, Ewha Woman’s University, Seoul, Republic of Korea; the Department of Anatomy (I.-S.P.), Inha University College of Medicine, Incheon, Republic of Korea; and the Department of Physiology and Biophysics (J.H.Y.), University of Southern California Keck School of Medicine, Los Angeles.

* To whom correspondence should be addressed. E-mail: jypark{at}amc.seoul.kr.

Objective--Lipid accumulation in vascular endothelial cells may play an important role in the pathogenesis of atherosclerosis in obese subjects. We showed previously that {alpha}-lipoic acid (ALA) activates AMP-activated protein kinase (AMPK) and reduces lipid accumulation in skeletal muscle of obese rats. Here, we investigated whether ALA improves endothelial dysfunction in obese rats by activating AMPK in endothelial cells.

Methods and Results--Endothelium-dependent vascular relaxation was impaired, and the number of apoptotic endothelial cells was higher in the aorta of obese rats compared with control rats. In addition, triglyceride and lipid peroxide levels were higher, and NO synthesis was lower. Administration of ALA improved all of these abnormalities. AMPK activity was lower in aortic endothelium of obese rats, and ALA normalized it. Incubation of human aortic endothelial cells with ALA activated AMPK and protected cells from linoleic acid-induced apoptosis. Dominant-negative AMPK inhibited the antiapoptotic effects of ALA.

Conclusions--Reduced AMPK activation may play an important role in the genesis of endothelial dysfunction in obese rats. ALA improves vascular dysfunction by normalizing lipid metabolism and activating AMPK in endothelial cells.
Key words: {alpha}-lipoic acid • endothelium • AMPK • oxidative stress • vascular dysfunction




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