Adenosine A_2A receptor modulates vascular response in soluble epoxide hydrolase-null mice through CYP-epoxygenases and PPARγ

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 A₁AR and PPARγ (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 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 A_2A AR, CYP2J, and PPARγ, and the downregulation of A₁ AR and PPARα.