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).

A 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.

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.