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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL056670-01A2
Application #
2697202
Study Section
Metabolism Study Section (MET)
Project Start
1998-07-10
Project End
2002-06-30
Budget Start
1998-07-10
Budget End
1999-06-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
VanRollins, Mike; VanderNoot, Victoria A (2003) Simultaneous resolution of underivatized regioisomers and stereoisomers of arachidonate epoxides by capillary electrophoresis. Anal Biochem 313:106-16
Vandernoot, Victoria A; VanRollins, Mike (2002) Capillary electrophoresis of cytochrome P-450 epoxygenase metabolites of arachidonic acid. 2. Resolution of stereoisomers. Anal Chem 74:5866-70
Ye, Dan; Zhang, David; Oltman, Christine et al. (2002) Cytochrome p-450 epoxygenase metabolites of docosahexaenoate potently dilate coronary arterioles by activating large-conductance calcium-activated potassium channels. J Pharmacol Exp Ther 303:768-76
Lu, Tong; VanRollins, Mike; Lee, Hon-Chi (2002) Stereospecific activation of cardiac ATP-sensitive K(+) channels by epoxyeicosatrienoic acids: a structural determinant study. Mol Pharmacol 62:1076-83
VanderNoot, Victoria A; VanRollins, Mike (2002) Capillary electrophoresis of cytochrome P-450 epoxygenase metabolites of arachidonic acid. 1. Resolution of regioisomers. Anal Chem 74:5859-65
Lu, T; Katakam, P V; VanRollins, M et al. (2001) Dihydroxyeicosatrienoic acids are potent activators of Ca(2+)-activated K(+) channels in isolated rat coronary arterial myocytes. J Physiol 534:651-67
Zhang, Y; Oltman, C L; Lu, T et al. (2001) EET homologs potently dilate coronary microvessels and activate BK(Ca) channels. Am J Physiol Heart Circ Physiol 280:H2430-40
Fang, X; Kaduce, T L; VanRollins, M et al. (2000) Conversion of epoxyeicosatrienoic acids (EETs) to chain-shortened epoxy fatty acids by human skin fibroblasts. J Lipid Res 41:66-74
Weintraub, N L; Fang, X; Kaduce, T L et al. (1999) Epoxide hydrolases regulate epoxyeicosatrienoic acid incorporation into coronary endothelial phospholipids. Am J Physiol 277:H2098-108
Lee, H C; Lu, T; Weintraub, N L et al. (1999) Effects of epoxyeicosatrienoic acids on the cardiac sodium channels in isolated rat ventricular myocytes. J Physiol 519 Pt 1:153-68

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