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Balz Frei
Director and Endowed Chair, Linus Pauling Institute
Professor, Biochemistry and Biophysics
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RESEARCH:
The research program in my laboratory is aimed at understanding the mechanisms of oxidative stress in atherosclerosis and coronary artery disease (CAD), and the ameliorating effects of dietary and metabolic antioxidants, dietary supplements, and metal chelators. One of the earliest events in atherosclerosis is dysfunction of the endothelium, leading to recruitment of monocytes to the arterial wall. Once trapped in the arterial wall, monocytes initiate an inflammatory response and eventually give rise to lipid-laden foam cells. In addition, endothelial dysfunction is associated with decreased nitric oxide synthesis and impaired vasodilation, which are important causal factors in hypertension. We are performing biochemical, cell biological, and animal studies to investigate the mechanisms and consequences of endothelial dysfunction, the role of pro-oxidant transition metals like iron and copper, and the effectiveness of ascorbic acid, lipoic acid, and other antioxidants in ameliorating endothelial dysfunction.
In collaboration with investigators at Boston University School of Medicine, we have discovered that vitamin C improves endothelial function and vasodilation in patients with CAD or coronary risk factors, and lowers blood pressure in moderately hypertensive patients. Work in our laboratory using human aortic endothelial cells has shown that metal chelators, lipoic acid, and flavonoids, but not vitamin C or glutathione, can inhibit the expression of endothelial adhesion molecules, which are responsible for monocyte recruitment to the arterial wall. We are now studying the cellular mechanisms underlying these beneficial effects on adhesion molecule expression, in particular inhibition of redox-sensitive cell signaling mechanisms and transcription factor activation. In addition, we are studying whether metal chelators and lipoic acid can exert anti-inflammatory and anti-atherogenic effects in transgenic mouse models by inhibiting adhesion molecule expression. These studies will also address the question of whether chelation therapy with EDTA or desferrioxamine (Deferal®), currently used in complementary and alternative medicine, is safe and efficacious in inhibiting atherosclerosis.
We also have discovered that consumption of fructose-rich foods, such as apples and fruits in general, causes plasma levels of uric acid to increase. Uric acid is a metabolic antioxidant, the potential health effects of which are poorly understood. While excessive uric acid levels cause gout, elevated uric acid levels have been associated with protection against multiple sclerosis and rheumatoid arthritis. In contrast, uric acid has been claimed to be an independent risk factor for CAD, but the evidence is inconclusive and controversial. Therefore, we are planning to examine the role of uric acid in endothelial adhesion molecule expression, inflammation, and atherosclerosis. Uric acid may also inhibit the degradation of extracellular matrix proteins in atherosclerotic lesions, which might prevent these lesions from rupturing and causing a myocardial infarction or stroke. The ultimate goal of our studies is to better understand the mechanisms of endothelial dysfunction and atherosclerosis and to find new, effective strategies to prevent and treat CAD by diet, dietary supplements, and therapeutic agents.