title: Vascular endothelial over-expression of soluble epoxide hydrolase (Tie2-sEH) enhances adenosine A1receptor-dependent contraction in mouse mesenteric arteries: role of ATP-sensitive K+channels.
abstract: Soluble epoxide hydrolase (sEH) converts epoxyeicosatrienoic acids that are endothelium-derived hyperpolarizing factors into less active dihydroxyeicosatrienoic acids. Previously, we reported a decrease in adenosine A1receptor (A1AR) protein levels in sEH knockout (sEH-/-) and an increase in sEH and A1AR protein levels in A2AAR-/-mice. Additionally, KATPchannels are involved in adenosine receptor (AR)-dependent vascular relaxation. Thus, we hypothesize that a potential relationship may exist among sEH over-expression, A1AR upregulation, inactivation of KATPchannels, and increased in vascular tone. We performed DMT myograph muscle tension measurements and western blot analysis in isolated mouse mesenteric arteries (MAs) from wild-type (WT) and endothelial over-expression of sEH (Tie2-sEH Tr) mice. Our data revealed that NECA (a non-selective adenosine receptors agonist)-induced relaxation was significantly reduced in Tie2-sEH Tr mice, and CCPA (A1AR agonist)-induced contraction was increased in Tie2-sEH Tr mice. A1AR-dependent contraction in Tie2-sEH Tr mice was significantly attenuated by pharmacological inhibition of CYP4A (HET0016, 10 µM), PKCα (GO6976, 1 µM), and ERK1/2 (PD58059, 1 µM). Our western blot analysis revealed significantly higher basal protein expression of CYP4A, A1AR, and reduced p-ERK in MAs of Tie2-sEH Tr mice. Notably, pinacidil (KATPchannel opener)-induced relaxation was also significantly reduced in MAs of Tie2-sEH Tr mice. Furthermore, KATPchannel-dependent relaxation in MAs was enhanced by inhibition of PKCα and ERK1/2 in WT but not Tie2-sEH Tr mice. In conclusion, our data suggest that over-expression of sEH enhances A1AR-dependent contraction and reduces KATPchannel-dependent relaxation in MAs. These results suggest a possible interaction between sEH, A1AR, and KATPchannels in regulating vascular tone.
authors.affiliation: Department of Physiology and Pharmacology, College of Medicine, West Virginia University, Morgantown, WV, USA.
authors.forename: Vishal R
authors.initials: VR
authors.lastname: Yadav
authors.affiliation: Department of Pharmaceutical Sciences, Center for Basic and Translational Stroke Research, Health Science Center-North, School of Pharmacy, West Virginia University, Biomedical Research Building, 2nd floor, Room # 220, 1 Medical Center Drive, PO Box 9530, Morgantown, WV, 26506-9530, USA.
authors.forename: Ka L
authors.initials: KL
authors.lastname: Hong
authors.affiliation: Division of Intramural Research, NIEHS/NIH, Research Triangle Park, NC, USA.
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.affiliation: Department of Pharmaceutical Sciences, Center for Basic and Translational Stroke Research, Health Science Center-North, School of Pharmacy, West Virginia University, Biomedical Research Building, 2nd floor, Room # 220, 1 Medical Center Drive, PO Box 9530, Morgantown, WV, 26506-9530, USA. mnayeem@hsc.wvu.edu.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Nayeem
mesh_terms: D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D042926:Cytochrome P-450 CYP4A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000096:biosynthesis* / Q000235:genetics; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism*; D008638:Mesenteric Arteries / Q000201:enzymology*; D051379:Mice; D008822:Mice, Transgenic; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000378:metabolism*; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism; D014661:Vasoconstriction
chemical_list: D058907:Adenosine A1 Receptor Agonists; D004791:Enzyme Inhibitors; D054086:KATP Channels; D043682:Receptor, Adenosine A1; D042926:Cytochrome P-450 CYP4A; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; C496630:Prkca protein, mouse; D051571:Protein Kinase C-alpha; D048052:Mitogen-Activated Protein Kinase 3; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse
keywords: A1AR; Contraction; KATP channel; Mesenteric artery; Relaxation; sEH