Alpha-lipoic acid prevents endothelial dysfunction in obese rats via activation of AMP-activated protein kinase.
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.


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.
Lee
Woo Je
WJ
Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Lee
In Kyu
IK
Kim
Hyoun Sik
HS
Kim
Yun Mi
YM
Koh
Eun Hee
EH
Won
Jong Chul
JC
Han
Sung Min
SM
Kim
Min-Seon
MS
Jo
Inho
I
Oh
Goo Taeg
GT
Park
In-Sun
IS
Youn
Jang Hyun
JH
Park
Seong-Wook
SW
Lee
Ki-Up
KU
Park
Joong-Yeol
JY
D000091162:AMP-Activated Protein Kinase Kinases; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018014:Gene Transfer Techniques; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000502:physiology; D019255:NADPH Oxidases / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009765:Obesity / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020334:Rats, Inbred OLETF; D008063:Thioctic Acid / Q000378:metabolism* / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D014280:Triglycerides; D008063:Thioctic Acid; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases