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

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17 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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