Adenosine A2A receptor modulates vascular response in soluble epoxide hydrolase-null mice through CYP-epoxygenases and PPARγ

Mohammed A. Nayeem, Isha Pradhan, S. Jamal Mustafa, Christophe Morisseau, J R Falck, Darryl C. Zeldin

Research output: Contribution to journalArticle

13 Scopus citations


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 A2A adenosine receptors (AR) via CYP-epoxygenases and peroxisome proliferator-activated receptor γ (PPARγ). sEH-/- showed an increase in A2A AR, CYP2J, and PPARγ by 31%, 65%, and 36%, respectively, and a decrease in A1AR and PPARγ (30% and 27%, respectively) vs. sEH+/+. 5'-N-ethylcarboxamidoadenosine (NECA, an adenosine receptor agonist), CGS 21680 (A2A 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 (A2A 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 PPARα-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 A2A AR, CYP2J, and PPARγ, and the downregulation of A1 AR and PPARα.

Original languageEnglish (US)
Pages (from-to)R23-R32
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Issue number1
StatePublished - Jan 1 2013


  • Adenosine A receptor
  • Adenosine A receptor
  • CYP2J5-epoxgenase;ω-hydroxylase
  • Contraction
  • Relaxation
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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