Office: 571 Weniger Hall
Telephone: (541) 737-5078
Fax: (541) 737-5077
Email Address: balz.frei@oregonstate.edu
Mailing/Express Delivery Address:
Balz Frei, Ph.D.
Linus Pauling Institute
Oregon State University
571 Weniger Hall
Corvallis, OR 97331-6512
| 1983-86 | Ph.D. student, Swiss Federal Institute of Technology, Zürich, Switzerland |
| 1987-90 | Post-doctoral fellow, Division of Biochemistry and Molecular Biology, University of California, Berkeley, CA (Bruce N. Ames, sponsor) |
| 1990 (summer) | Visiting Scholar, The Heart Research Institute, Sydney, NSW, Australia |
| 1990-94 | Assistant Professor of Nutrition, Department of Nutrition, Harvard School of Public Health, Boston, MA |
| 1992-94 | Assistant Professor of Toxicology, Department of Molecular and Cellular Toxicology, Harvard School of Public Health, Boston, MA |
| 1994-97 | Associate Professor of Medicine and Biochemistry, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA |
| 1997-present | Professor, Biochemistry and Biophysics, Director and Endowed Chair, Linus Pauling Institute, Oregon State University, Corvallis, OR |
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.
Archives of Biochemistry and Biophysics (1993-96)
Redox Report (1996-present)
Free Radical Biology & Medicine (1997-present)
FASEB Journal (2001-present)
American Journal of Clinical Nutrition (2002-2004)
P01 AT002034 (Frei)
NIH/NCCAM
Center of Excellence for Research on Complementary and Alternative Medicine
Antioxidant Therapies (CERCAT)
Period: 09/30/03-05/31/08
The major goals of this program project grant are to determine the roles of
oxidative and nitrative stress in animal models of atherosclerosis, Lou Gehrig's
disease, and aging, and the protective effects of lipoic acid and metal chelation
therapy. The major goals of Project 1 (Metal Chelators and Thiols in Endothelial
Function and CVD) are to understand the mechanisms by which thiol compounds
and transition metals affect redox-sensitive cellular signaling and transcription
factor activation; and to investigate in animal models of inflammation and atherosclerosis
whether lipoic acid and metal chelators exert anti-inflammatory and anti-atherosclerotic
effects by inhibiting cellular adhesion molecule expression.
Roles: Program Director, Project 1
Leader (Metal Chelators and Thiols in Endothelial Function and CVD), and Administrative
Core Director
T32 AT002688 (Oken)
NIH/NCCAM
CAM: Neuroscience and Stress
Period: 04/01/05-03/31/10
The major goal of this grant is to train graduate students and post-doctoral
fellows in basic and applied research related to complementary medicine and
either neurology or stress, including oxidative/nitrative and toxicological
stresses.
Role: PI on Oregon State University subcontract, Training Faculty
Widlansky, M.E., Duffy, S.J., Hamburg, N.M., Gokce, N., Warden, B.A., Wiseman, S., Keaney, J.F., Jr., Frei, B., and Vita, J.A. (2005) Effects of black tea consumption on plasma catechins and markers of oxidative stress and inflammation in patients with coronary artery disease. Free Rad. Biol. Med. 38, 499-506.
Hathcock, J.N., Azzi, A., Blumberg, J., Bray, T., Dickinson, A., Frei, B., Jialal, I., Johnston, C.S., Kelly, F.J., Kraemer, K., Packer, L., Parthasarathy, S., Sies, H., and Traber, M.G. (2005) Vitamins E and C are safe across a broad range of intakes. Am. J. Clin. Nutr. 81, 736-745.
Stone, P.H., Lloyd-Jones, D.M., Kinlay, S., Frei, B., Carlson, W., Rubenstein, J., Andrews, T.C., Johnstone, M., Sopko, G., Cole, H., Orav, J., Selwyn, A.P., Creager, M.A.; Vascular Basis Study Group. (2005) Effect of intensive lipid lowering, with or without antioxidant vitamins, compared with moderate lipid lowering on myocardial ischemia in patients with stable coronary artery disease: the Vascular Basis for the Treatment of Myocardial Ischemia Study. Circulation 111, 1747-1755.
Doulias, P.T., Nousis, L., Zhu, B.Z., Frei, B., and Galaris, D. (2005) Protection by tropolones against H2O2-induced DNA damage and apoptosis in cultured Jurkat cells. Free Radic. Res. 39, 125-135.
Back, S.A., Luo, N.L., Mallinson, R.A., O'Malley, J.P., Wallen, L.D., Frei, B., Morrow, J.D., Petito, C.K., Roberts, C.T., and Murdoch, G.H., and Montine, T.J. (2005) Selective vulnerability of preterm white matter to oxidative damage defined by F2-isoprostanes. Ann. Neurol. 58, 108-120.
Higdon, J.V. and Frei, B. (2005) Is there a gender difference in the effect of antioxidants on cancer risk? Br. J. Nutr. 93, 139-140.
Sowell, J., Conway, H.M., Bruno, R.S., Traber, M.G., Frei, B., and Stevens, J.F. (2005) Ascorbylated 4-hydroxy-2-nonenal as a potential biomarker of oxidative stress response. J. Chromatogr. B 15, 139-145.
Hathcock, J.N., Frei, B., Lawson, S., and Johnston, C. (2005) Safety of Vitamin C: Reply to L Massey. Am. J. Clin. Nutr. 82, 489.
Higdon, J.V. and Frei, B. (2006) Coffee and health: A review of recent human research. Crit. Rev. Food Sci. Nutr. 46, 101-123.
Taylor, A.W., Bruno, R.S., Frei, B., and Traber, M.G. (2006) Benefits of prolonged gradient separation for HPLC-MS-MS quantitation of plasma 15-series F2-isoprostanes. Anal. Biochem. 350, 41-51.
Popkin, B.M., Armstrong, L.E., Bray, G.M., Caballero, B., Frei, B., and Willett, W.C. (2006) A new proposed guidance system for beverage consumption in the United States. Am. J. Clin. Nutr. 83, 529-542.
Gaut, J.P., Belaaouaj, A., Byun, J., Roberts, L.J., II, Maeda, N., Frei, B., and Heinecke, J.W. (2006) Vitamin C fails to protect amino acids and lipids from oxidation during acute inflammation. Free Rad. Biol. Med. 40, 1494-1501.
Smith, A.R., Visioli, F., Frei, B., and Hagen, T.M. (2006) Age-related changes in endothelial nitric oxide synthase phosphorylation and nitric oxide dependent vasodilation: evidence for a novel mechanism involving sphingomyelinase and ceramide-activated phosphatase 2A. Aging Cell 5, 391-400.
Lotito, S.B. and Frei, B. (2006) Dietary flavonoids attenuate TNFalpha-induced adhesion molecule expression in human aortic endothelial cells: Structure-function relationships and activity after first pass metabolism. J. Biol. Chem. 281, 37102-37110.
Li, L. and Frei, B. (2006) Iron chelation inhibits NF-kappa B-mediated adhesion molecule expression by inhibiting p22phox protein expression and NADPH oxidase activity. Arterioscler. Thromb. Vasc. Biol. 26, 2638-2643.
Lotito, S.B. and Frei, B. (2006) Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: cause, consequence, or epiphenomenon? Free Radic. Biol. Med. 41, 1727-1746.
Zhu, B., Zhao, H.T., Kalyanaraman, B., Liu, J., Guo-Qiang Shan, G.Q., Du, Y.G., and Frei, B. (2007) Mechanism of metal-independent decomposition of organic hydroperoxides and formation of alkoxyl radicals by halogenated quinones. Proc. Natl. Acad. Sci. USA 104, 3698-3702.
Zhang, W., Wei, H., Hagen, T., and Frei, B. (2007) Alpha-lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway. Proc. Natl. Acad. Sci. USA 104, 4077-4082.
Blumberg, J.B. and Frei, B. (2007) Why clinical trials of vitamin E and cardiovascular diseases may be fatally flawed. Commentary on "The relationship between dose of vitamin E and suppression of oxidative stress in humans". Free Radic. Biol. Med. 43, 1374-1376.
Zhang, W.J., Bird, K.E., McMillen, T.S., Leboeuf, R.C., Hagen, T.M., and Frei B. (2008) Dietary alpha-lipoic acid supplementation inhibits atherosclerotic lesion development in apolipoprotein E deficient and apolipoprotein E/low-density lipoprotein receptor deficient mice. Circulation 117, 421-428.
Traber, M.G., Frei, B., and Beckman, J.S. (2008) Vitamin E revisited: do new data validate benefits for chronic disease prevention? Curr. Opin. Lipidol. 19, 30-38.
