Adenosine A(2A) receptor modulates vascular response in soluble epoxide hydrolase-null mice through CYP-epoxygenases and PPAR gamma

Nayeem MA, Pradhan I, Mustafa SJ, Morisseau C, Falck JR, Zeldin DC. AdenosineA(2A) receptor modulates vascular response in soluble epoxide hydrolase-null mice through CYP-epoxygenases and PPAR gamma. Am J Physiol Regul Integr Comp Physiol 304: R23-R32, 2013. First published November 14, 2012; doi:10.1152/ajpregu.00213.2012.-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 gamma (PPAR gamma). sEH(-/-) showed an increase in A(2A) AR, CYP2J, and PPAR gamma by 31%, 65%, and 36%, respectively, and a decrease in A(1)AR and PPAR gamma (30% and 27%, respectively) vs. sEH(-/-). 5=-N-ethylcarboxamidoadenosine (NECA, an adenosine receptor agonist), CGS 21680 (A2A AR-agonist), and GW 7647 (PPAR gamma-agonist)-induced responses were tested with nitro-L-arginine methyl ester (L-NAME) (NO-inhibitor; 10(-4) M), ZM-241385, SCH58261 (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 mu M) or trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB, sEH-inhibitors; 10(-5) M), and T0070907 (PPAR gamma-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). PPAR gamma-agonist did not relax as CGS 21680 (-2.48 +/- 1.1 vs. + 37.4 +/- 5.4%) in sEH(-/-), and PPAR gamma-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 PPAR gamma, and the downregulation of A(1) AR and PPAR alpha.