Cardiovascular disease is the leading cause of morbidity and mortality in the United States. Current evidence suggests that both inflammation and oxidative stress are crucial in atherogenesis and that dietary antioxidants may be beneficial. Since 1988 the candidate's group has made significant observations in the area, especially as it relates to patient oriented research. In this proposal, which is a logical extension, the following studies will be undertaken: 1) The effect of high dose alpha-tocopherol (AT) supplementation on LDL oxidation, monocyte pro-atherogenic activity and carotid atherosclerosis in patients with coronary artery disease; 2) The effect of pycnogenol alone and in combination with AT on measures of oxidative stress; 3) Interaction between N-3 PUFA and AT on inflammation and LDL oxidation; 4) The effect of HMG-CoA reductase inhibitors on plasma levels of remnant lipoproteins; 5) Evolving cardiovascular risk factors in African Americans and Caucasians; and 6) A dose response study on the effect of AT on inflammation. The measures of oxidative stress include plasma oxidation by assaying protein carbonyls, LDL oxidative susceptibility and the quantitation of urinary F2.isoprostanes. Inflammatory markers that will be studied include. plasma levels of soluble adhesion molecules s-ICAM, s-VCAM, sE-selectin and sP-selectin and C-reactive protein. The functions that will be assayed in activated monocytes are superoxide anion, IL-1beta, TNF-alpha, tissue factor, and monocyte endothelial adhesion. In Project V, in addition to studying measures of oxidative stress and inflammation, we will determine the role of homocysteine and Chlamydia pneumoniae in predicting atherosclerosis by EBCT. In Project VI mechanistic insights will be gained by studying PKC, 5-LO and NFkappa-b activity. These studies coupled with didactic courses and clinical exposure at UT Southwestern provide an excellent training ground for mentorees in patient oriented research. The studies outlined in this proposal clearly enhance the long-term objectives of the PI, since his major interest is in the role of nutritional factors on lipoproteins and critical cells in atherogenesis. These studies in aggregate will definitely contribute to our understanding of atherosclerosis.
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