title: Adenosine A2A receptor modulates vascular response in soluble epoxide hydrolase-null mice through CYP-epoxygenases and PPARγ.
abstract: The interaction between adenosine and soluble epoxide hydrolase (sEH) in vascular response is not known. Therefore, we hypothesized that lack of sEH in mice enhances adenosine-induced relaxation through A(2A) adenosine receptors (AR) via CYP-epoxygenases and peroxisome proliferator-activated receptor γ (PPARγ). sEH(-/-) showed an increase in A(2A) AR, CYP2J, and PPARγ by 31%, 65%, and 36%, respectively, and a decrease in A(1)AR and PPARα (30% and 27%, respectively) vs. sEH(+/+). 5'-N-ethylcarboxamidoadenosine (NECA, an adenosine receptor agonist), CGS 21680 (A(2A) AR-agonist), and GW 7647 (PPARα-agonist)-induced responses were tested with nitro-l-arginine methyl ester (l-NAME) (NO-inhibitor; 10(-4) M), ZM-241385, SCH-58261 (A(2A) AR-antagonists; 10(-6) M), 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, an epoxyeicosatrienoic acid-antagonist; 10(-5) M), 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA; 10 μM) or trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB, sEH-inhibitors; 10(-5) M), and T0070907 (PPARγ-antagonist; 10(-7) M). In sEH(-/-) mice, ACh response was not different from sEH(+/+) (P > 0.05), and l-NAME blocked ACh-responses in both sEH(-/-) and sEH(+/+) mice (P < 0.05). NECA (10(-6) M)-induced relaxation was higher in sEH(-/-) (+12.94 ± 3.2%) vs. sEH(+/+) mice (-5.35 ± 5.2%); however, it was blocked by ZM-241385 (-22.42 ± 1.9%) and SCH-58261(-30.04 ± 4.2%). CGS-21680 (10(-6) M)-induced relaxation was higher in sEH(-/-) (+37.4 ± 5.4%) vs. sEH(+/+) (+2.14 ± 2.8%). l-NAME (sEH(-/-), +30.28 ± 4.8%, P > 0.05) did not block CGS-21680-induced response, whereas 14,15-EEZE (-7.1 ± 3.7%, P < 0.05) did. Also, AUDA and t-AUCB did not change CGS-21680-induced response in sEH(-/-) (P > 0.05), but reversed in sEH(+/+) (from +2.14 ± 2.8% to +45.33 ± 4.1%, and +63.37 ± 7.2, respectively). PPARα-agonist did not relax as CGS 21680 (-2.48 ± 1.1 vs. +37.4 ± 5.4%) in sEH(-/-), and PPARγ-antagonist blocked (from +37.4 ± 5.4% to +9.40 ± 3.1) CGS 21680-induced relaxation in sEH(-/-). Our data suggest that adenosine-induced relaxation in sEH(-/-) may depend on the upregulation of A(2A) AR, CYP2J, and PPARγ, and the downregulation of A(1) AR and PPARα.
authors.affiliation: Dept. of Physiology and Pharmacology, Center for Cardiovascular and Respiratory Sciences, West Virginia University, Morgantown, USA. mnayeem@hsc.wvu.edu
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Nayeem
authors.forename: Isha
authors.initials: I
authors.lastname: Pradhan
authors.forename: S Jamal
authors.initials: SJ
authors.lastname: Mustafa
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000235:genetics / Q000502:physiology*; D005260:Female; D020868:Gene Silencing; D007850:Lauric Acids / Q000494:pharmacology; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010105:Oxygenases / Q000502:physiology*; D047495:PPAR gamma / Q000502:physiology*; D010627:Phenethylamines / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C504897:12-(3-adamantan-1-ylureido)dodecanoic acid; C494022:14,15-eicosa-5-enoic acid; C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D001549:Benzamides; D001565:Benzoates; D002087:Butyrates; D004791:Enzyme Inhibitors; C453899:GW 7647; D007850:Lauric Acids; D047495:PPAR gamma; D010627:Phenethylamines; D010671:Phenylurea Compounds; D011725:Pyridines; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; C458508:T 0070907; D014227:Triazines; D014230:Triazoles; D014665:Vasodilator Agents; C097270:ZM 241385; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D019830:Adenosine-5'-(N-ethylcarboxamide); D014508:Urea; D010105:Oxygenases; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid; D000241:Adenosine; D000218:Adamantane; D019331:NG-Nitroarginine Methyl Ester