Lipoic acid effects on established atherosclerosis.
OBJECTIVE
Alpha-lipoic acid (LA) is a commonly used dietary supplement that exerts anti-oxidant and anti-inflammatory effects in vivo and in vitro. We investigated the mechanisms by which LA may confer protection in models of established atherosclerosis.


METHODS
Watanabe heritable hyperlipidemic (WHHL) rabbits were fed with high cholesterol chow for 6 weeks and then randomized to receive either high cholesterol diet alone or combined with LA (20mg/kg/day) for 12 weeks. Vascular function was analyzed by myography. The effects of LA on T cell migration to chemokine gradients was assessed by Boyden chamber. NF-kappaB activation was determined by measuring translocation and electrophoresis migration shift assay (EMSA).


RESULTS
LA decreased body weight by 15+/-5% without alterations in lipid parameters. Magnetic Resonance Imaging (MRI) analysis demonstrated that LA reduced atherosclerotic plaques in the abdominal aorta, with morphological analysis revealing reduced lipid and inflammatory cell content. Consistent with its effect on atherosclerosis, LA improved vascular reactivity (decreased constriction to angiotensin II and increased relaxation to acetylcholine and insulin), inhibited NF-kappaB activation, and decreased oxidative stress and expression of key adhesion molecules in the vasculature. LA reduced T cell content in atherosclerotic plaque in conjunction with decreasing ICAM and CD62L (l-selectin) expression. These effects were confirmed by demonstration of a direct effect of LA in reducing T cell migration in response to CCL5 and SDF-1 and decreasing T cell adhesion to the endothelium by intra-vital microscopy.


CONCLUSIONS
The present findings offer a mechanistic insight into the therapeutic effects of LA on atherosclerosis.
Ying
Zhekang
Z
Davis Heart Lung Research Institute, College of Medicine, and Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio 43210-1252, USA.
Kherada
Nisharahmed
N
Farrar
Britten
B
Kampfrath
Thomas
T
Chung
Yiucho
Y
Simonetti
Orlando
O
Deiuliis
Jeffrey
J
Desikan
Rajagopal
R
Khan
Bobby
B
Villamena
Frederick
F
Sun
Qinghua
Q
Parthasarathy
Sampath
S
Rajagopalan
Sanjay
S
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001786:Blood Glucose / Q000032:analysis; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008074:Lipoproteins / Q000097:blood; D008297:Male; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D008063:Thioctic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D051996:Transcription Factor RelA / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001786:Blood Glucose; D002791:Cholesterol, Dietary; D007328:Insulin; D008074:Lipoproteins; D051996:Transcription Factor RelA; D008063:Thioctic Acid