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The Role of Lipoic Acid in Inflammation and Atherosclerosis

Weijian Zhang, M.D., Ph.D.
LPI Assistant Professor (Sr. Res.)

Summary: Inflammation is now recognized as an important contributing factor to atherosclerosis and heart disease. Inflammatory molecules stimulate events that lead to the recruitment of white blood cells into the blood vessel wall, where they give rise to abnormal foam cells and initiate the development of atherosclerotic lesions. In cell cultures, alpha-lipoic acid and metal-binding substances called metal chelators inhibit white blood cell recruitment. We are now investigating whether alpha-lipoic acid and metal chelators can inhibit atherosclerosis in animal models and in humans.

Atherosclerosis and its associated vascular complications are the principal cause of cardiovascular and cerebrovascular diseases (CVDs) leading to myocardial infarction (heart attacks) and stroke (“brain attacks”), respectively. CVDs are the principal cause of death in Western civilizations, accounting for more than 40% of all deaths. According to the American Heart Association’s 2003 Heart and Stroke Statistical Update, almost 62 million Americans suffer from CVDs, which have been the number one killer in the U.S. for more than nine decades. Epidemiological studies over the past 50 years have revealed numerous risk factors for atherosclerosis, which can be grouped into factors with an important genetic component and those that are largely environmental. These environmental factors are of great importance for the general population. About 70% of strokes and 80% of heart attacks are potentially preventable by diet and lifestyle modifications, including nonsmoking, a healthy diet (low intakes of saturated and trans fat, low glycemic load, and adequate intakes of fruits and vegetables, cereal fiber, and unsaturated fat, especially omega-3 fatty acids), a healthy weight (body mass index <25 kg/m2), regular exercise, and moderate alcohol consumption.

Most of these environmental factors affect CVD risk by improving one’s general health status, including preventing infection and inflammation and reducing oxidative stress by bolstering antioxidant defenses. Compelling evidence now points to cardiovascular inflammation and resultant oxidative stress as important triggers in the complex chain of events leading to atherosclerosis.

Inflammation is a complicated process that develops in response to infection or injury. Damaged tissue releases chemicals that attract white blood cells, which then attack microorganisms and consume damaged cells. During this process, hormone-like signaling molecules called cytokines are produced that accelerate inflammation. One cytokine, IL-6, stimulates the synthesis of C-reactive protein, which is a biomarker for inflammation (see box below).

Longitudinal cross section of blood vesselA crucial initiating event in atherosclerosis is the interaction of white blood cells—monocytes and lymphocytes—with the endothelium, which is the cell layer of the blood vessel wall that faces the blood stream. Following adherence of these white blood cells to the endothelium, they migrate across the endothelium and into the arterial wall (see figure below). Once trapped in the arterial wall, the monocytes engorge oxidized (“bad”) cholesterol and are converted into fat-laden foam cells. Formation and aggregation of foam cells is the first manifestation of atherosclerosis, leading to the narrowing of the opening of the artery and, eventually, to full-blown CVD.

The adherence of monocytes to the endothelium and subsequent migration into the arterial wall are caused by presentation of “sticky” proteins called cellular adhesion molecules on the surface of endothelial cells. Inflammatory cytokines directly stimulate the production of these adhesion molecules. Furthermore, studies in patients and experimental animals have found that there is an abundance of adhesion molecules on arterial sites prone to atherosclerosis. For example, the very first change in the arterial wall in response to feeding rabbits a high-cholesterol diet is the presentation of adhesion molecules, even before foam cells and atherosclerotic lesions become discernable. Studies in mice have also found that genetic deficiencies of adhesion molecules are associated with significantly delayed atherosclerosis. Therefore, adhesion molecules may be an important target for the prevention and treatment of atherosclerosis and CVD.

What dietary or therapeutic agents might be able to block or inhibit production of endothelial adhesion molecules? Since regulation of these molecules has been related to inflammation and oxidative stress, antioxidants may exert inhibitory effects. To test this hypothesis, we investigated the role of three antioxidants—alpha-lipoic acid, glutathione, and vitamin C—in the production of adhesion molecules in cultured human endothelial cells and in mice.

Alpha-lipoic acid is a naturally occurring compound that appears to be useful in treating pathologies associated with oxidative stress. For example, alpha-lipoic acid has been safely used for more than 30 years in Europe to prevent and treat complications associated with diabetes, such as protein glycation, abnormal glucose utilization, polyneuropathy, and cataracts. Alpha-lipoic acid can also bind to, or chelate, metals like iron and copper. Exogenously supplied lipoic acid is readily absorbed by cells and tissues and then rapidly reduced to its potent antioxidant form, dihydrolipoate.

We found that alpha-lipoic acid significantly inhibits both the formation of adhesion molecules and the adherence of monocytes to endothelial cells in culture. However, to our surprise these processes were not influenced by vitamin C or glutathione, suggesting that general oxidative stress does not play a significant role in the activation of human endothelial cells to produce adhesion molecules. Because alpha-lipoic acid also is a good metal chelator, we hypothesized that metals may be involved in the production of adhesion molecules. To test this hypothesis, we added compounds to the cell culture that specifically chelate iron or copper. Our results showed that treatment with metal chelators also inhibits the production of adhesion molecules and monocyte adherence to cultured endothelial cells, thus supporting our hypothesis that the metal-chelating activity of alpha-lipoic acid may be responsible for its salubrious effects on endothelial cell function.

In another set of experiments, we found that treatment of mice with alpha-lipoic acid strongly inhibited the production of adhesion molecules in response to a bacterial toxin called LPS. Moreover, alpha-lipoic acid significantly protected against death induced by large doses of LPS (also called “septic shock”). These studies provide the first evidence that alpha-lipoic acid inhibits LPS-induced endothelial activation in animals, suggesting a possible role for alpha-lipoic acid in the prevention and treatment of atherosclerosis and inflammatory conditions in humans.

There is now widespread appreciation that atherosclerosis is a chronic inflammatory disease in which monocytes interact with activated endothelium. Our data provide new evidence that alpha-lipoic acid, due to its metal chelating and, possibly, antioxidant functions, inhibits endothelial activation both in cultured human cells and in mice, thus potentially delaying atherosclerosis and CVD. Elucidating the precise mechanisms by which alpha-lipoic acid disrupts endothelial adhesion molecule expression will be important in identifying other agents that may be specific and effective in inhibiting the initiation and progression of atherosclerosis and other inflammatory diseases.

C-reactive Protein

C-reactive protein, or CRP, is produced in the liver and has emerged as a strong predictor of clinical events of cardiovascular diseases, such as heart attacks and stroke, even in cases where cholesterol levels may be normal.  For this reason, CRP assays may become a routine part of blood tests for determining CVD risk.  CRP levels in the blood are normally undetectable or very low; high levels are strongly associated with inflammation.  CRP is a biomarker for the metabolic disorder called syndrome X, type II diabetes, hypertension, and CVD, and is linked to body mass.  CRP levels may be lowered by physical activity, anti-inflammatory drugs like aspirin, and through weight loss in obese individuals.  Recent studies have detected CRP in atherosclerotic lesions, where it has been found to attract white blood cells called monocytes and to increase the production of adhesion molecules in endothelial cells (see accompanying article).  Although few studies have investigated the relationship between antioxidants and CRP, a small study on patients with peripheral artery disease by Belgian researchers recently found that CRP levels in blood were inversely correlated with vitamin C levels.  This finding, along with other evidence on vitamin E, suggests that antioxidants may play an anti-inflammatory role.

For additional information on lipoic acid, see the Linus Pauling Institute's Micronutrient Information Center.

Last updated May, 2003

Micronutrient Research for Optimum Health

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