Elsevier

Life Sciences

Volume 86, Issues 3–4, 16 January 2010, Pages 95-102
Life Sciences

Lipoic acid effects on established atherosclerosis

https://doi.org/10.1016/j.lfs.2009.11.009Get rights and content

Abstract

Aims

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.

Main 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 (20 mg/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-κB activation was determined by measuring translocation and electrophoresis migration shift assay (EMSA).

Key findings

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-κB 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.

Significance

The present findings offer a mechanistic insight into the therapeutic effects of LA on atherosclerosis.

Introduction

α-Lipoic acid (LA; 1,2-dithiolane-3-pentanoic acid) is a naturally occurring disulfide compound commonly found in diet and is a necessary cofactor for mitochondrial enzymes α-ketoglutarate and pyruvate dehydrogenases in mammals (Reed et al. 1951). Various studies have shown that LA exerts powerful anti-inflammatory and anti-oxidant effects in vitro (Packer et al. 1995). Treatment of cultured monocytes with LA inhibits lipopolysaccharide-mediated induction of pro-inflammatory factors through up-regulation of the PI3 kinase-Akt pathway (Zhang et al. 2007). Consistent with these effects, LA has been shown to be protective in human diseases associated with abnormal oxidative stress and energy metabolism such as diabetes mellitus (Estrada et al., 1996, Henriksen et al., 1997), hyperhomocysteinemia (Baydas et al. 2002) and hypertension (Vasdev et al., 2000a, Vasdev et al., 2000b). Previous studies performed by our group have revealed that 4 weeks of dietary supplementation with LA in humans was sufficient to improve endothelial function in patients with metabolic syndrome (Sola et al. 2005). Prior studies with LA and atherosclerosis have tested the effects of the agent very early on in the life cycle of atherosclerosis development (Zhang et al. 2008) and have not tested the effects once atherosclerosis is established. In this study, we tested the hypothesis that oral supplementation of LA in the diet would inhibit established atherosclerosis and further investigated the mechanisms by which LA exerts these effects by parallel investigations on vascular inflammation and in particular the infiltration of T cells.

Section snippets

Methods

Organ chamber experiments were performed in the thoracic aorta of WHHL rabbits as detailed in online methods. In vivo Magnetic Resonance Imaging of the abdominal aorta was performed at various time points as shown in Supplementary Figure 1. Quantitative morphometry, lipid profiles, oxidative stress measures, quantitative real-time PCR western, NF-κB activation assays, intra-vital microscopy, and T cell migration assays are all described in the online Supplemental methods section.

Results

The study design of rabbit experiments is illustrated in Supplementary Figure 1. All rabbits were fed with high cholesterol chow for a period of 6 weeks prior to randomization to LA/control groups in order to hasten the development of plaque in this pre-disposed animal model. During this period the rabbit gained weight (2.62 ± 0.4 kg baseline and 2.96 ± 0.38 kg after 6 weeks of high cholesterol chow; n = 9; p < 0.05, paired Student's t-test for 6 weeks vs baseline). Dietary supplementation with LA started

Discussion

The present study has multiple findings that may have important implications for the treatment of human atherosclerosis using LA, a commonly used dietary supplement, at low doses. 1) LA decreases atherosclerotic plaque burden within a 12 week period with changes seen as early as 6 weeks; 2) Decreased plaque burden was paralleled by marked improvements in vascular function; 3) LA reduces NADPH oxidase dependent O2•− and NF-κB-mediated inflammatory responses, offering a molecular basis for the

Conflict of interest statement

There is no conflict of interest.

Acknowledgment

We are grateful to Aixia Wang for her valuable technique assistance. This study is supported by NIH grants R01ES013406 and R01ES015146 (S.R.) and RO1HL81248 awarded to Dr. Villamena. Qinghua Sun is supported by NIH KO1ES016588.

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