Participants in the regulation of vascular tone include remote influences (i.e., central nervous system, hormonal) and local factors (i.e., endothelium-derived relaxing and contracting factors). Recently, epoxyeicosatrienoic acids (EETs), cytochrome P-450- derived metabolites of arachidonic acid (AA), have been implicated as local participants in vasoregulation. EETs are produced by vascular endothelial cells and, in some studies, have been reported to relax blood vessels through activation of Kplus channels. By virtue of these properties, EETs are considered to be endothelium- deried hyperpolarizing factors. EETs have been suggested to contribute substantially to endothelium-dependent relaxation responses in epicardial coronary arteries and in the coronary microcirculation. However, no studies have been performed to directly examine responses to EETs in coronary microvessels. Moreover, little is known about the regulation of EET metabolism and uptake by blood vessels. Although vascular cells rapidly convert EETs to dihydroxyeicosatrienoic acids (DHETs) and rapidly incorporate EETs into cell lipids, the importance of these processes to the vascular actions of EETs is unknown. Preliminary studies from our laboratory indicate that 1) EETs are potent dilators of coronary microvessels, producing significant vasodilatation at picomolar concentrations 2) DHETs produce similar amounts of porcine coronary artery relaxation as EETs and 3) incubation of porcine coronary arteries with EETs to promote incorporation into cell lipids results in potentiation of relaxation to bradykinin, a compound which stimulates endothelial cell phospholipid hydrolysis. We hypothesize that EETs and DHETs contribute importantly to the physiologic and pathophysiologic vasoregulation of the coronary circulation. In order to elucidate the regulatory roles of EETs and DHETs in the coronary circulation, we propose to determine the mechanisms by which EETs relax coronary microvessels, define the contribution of DHETs to EET-mediated relaxation of coronary arteries, and investigate the mechanisms which regulate EET incorporation into and release from coronary artery endothelial cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL049264-10
Application #
6495735
Study Section
Project Start
2001-09-01
Project End
2003-08-31
Budget Start
Budget End
Support Year
10
Fiscal Year
2001
Total Cost
$73,467
Indirect Cost
Name
University of Iowa
Department
Type
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Blomkalns, Andra L; Stoll, Lynn L; Shaheen, Wassim et al. (2011) Low level bacterial endotoxin activates two distinct signaling pathways in human peripheral blood mononuclear cells. J Inflamm (Lond) 8:4
Spector, Arthur A (2009) Arachidonic acid cytochrome P450 epoxygenase pathway. J Lipid Res 50 Suppl:S52-6
Li, Wei Gen; Gavrila, Dan; Liu, Xuebo et al. (2004) Ghrelin inhibits proinflammatory responses and nuclear factor-kappaB activation in human endothelial cells. Circulation 109:2221-6
Chang, Lin; Ren, Yongsheng; Liu, Xiuhua et al. (2004) Protective effects of ghrelin on ischemia/reperfusion injury in the isolated rat heart. J Cardiovasc Pharmacol 43:165-70
Fang, Xiang; Weintraub, Neal L; McCaw, Ryan B et al. (2004) Effect of soluble epoxide hydrolase inhibition on epoxyeicosatrienoic acid metabolism in human blood vessels. Am J Physiol Heart Circ Physiol 287:H2412-20
Stoll, Lynn L; Denning, Gerene M; Li, Wei-Gen et al. (2004) Regulation of endotoxin-induced proinflammatory activation in human coronary artery cells: expression of functional membrane-bound CD14 by human coronary artery smooth muscle cells. J Immunol 173:1336-43
Spector, Arthur A; Fang, Xiang; Snyder, Gary D et al. (2004) Epoxyeicosatrienoic acids (EETs): metabolism and biochemical function. Prog Lipid Res 43:55-90
Chen, Ping; Hu, Shanming; Harmon, Shawn D et al. (2004) Metabolism of anandamide in cerebral microvascular endothelial cells. Prostaglandins Other Lipid Mediat 73:59-72
Nerheim, Pamela L; Meier, Jeffery L; Vasef, Mohammad A et al. (2004) Enhanced cytomegalovirus infection in atherosclerotic human blood vessels. Am J Pathol 164:589-600
Li, Wei-Gen; Stoll, Lynn L; Rice, James B et al. (2003) Activation of NAD(P)H oxidase by lipid hydroperoxides: mechanism of oxidant-mediated smooth muscle cytotoxicity. Free Radic Biol Med 34:937-46

Showing the most recent 10 out of 138 publications