Diets Rich in polyunsaturated fatty acids (PUFA) are anti-atherogenic in humans, in part due to cholesterol lowering effects. Diets rich in n-3 PUFA have been found to inhibit atherosclerosis in animal models without reducing plasma cholesterol levels. Multiple studies have suggested that dietary n-3 fatty acids increase the vascular levels of oxidized PUFA. However, the identity of these oxidized PUFA is unclear, and it is thus uncertain whether they are pro- or anti-atherogenic. We hypothesize that hypercholesterolemia and dietary n-3 PUFA act together to elevate the concentrations of PUFA epoxides/diols in plasma lipoproteins, platelets and the vascular wall. Sustained exposures to these compounds will cause arachidonate to be replaced by PUFA epoxides and diols, and thus alter secondary messenger production. The platelet aggregation responses may become blunted, and the endothelial production of prostacyclin and endothelial-dependent hyperpolarizing factor (EDHF) enhanced. Thus, expoxides of dietary n-3 PUFA may contribute to the anti-thrombotic and anti-atherosclerotic effects of marine diets even when accompanied by elevated plasma cholesterol levels. We will determine whether: 1. (a) Perfused coronary arteries acutely take up and incorporate epoxides and diols into phospholipids, and (b) Receptor agonists (bradykinin and metacholine) stimulate the hydrolysis of coronary phospholipids and the release of arachidonate epoxides and diols, and (c) Epoxides and diols are stored in vivo in coronary arteries; 2. Bradykinin stimulates the release of esterified arachidonate epoxides and diols in amount adequate to explain their potentiation of bradykinn-induced relaxation of coronary artieries; 3. Epoxides and diols derived from arachidonate and eichosapentaenoic acids potently dilate canine coronary microvessels; 4. Hypercholesterolemic patients ingesting dietary n-3 PUFA have (a) elevations in circulating concentrations of unesterified epoxides and diols to levels which inhibit platelet aggregation responses and dilate coronary microvessels, (b) Increased platelet levels of esterified epoxides and diols which are associated with decreased platelet responsiveness, (c) Increased platelet capacity to release epoxides and diols in response to thrombin, and (d) Increased plasma concentrations of epoxides and diols esterified to lipoproteins. Whether the changes in epoxide/diol concentrations correlate temporally with changes in platelet activation and triglyceridemia will also be determined. In summary, in contrast to prostaglandins and leukotrienes, PUFA epoxides appear to occur in tissues predominantly esterified to phospholipids. The above studies will study the consequences of this storage property in arteries and platelets, and provide a better understanding on how dietary PUFA may influence vascular disease in ways unrelated to plasma lo density lipoprotein levels.
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