Reduced coronary reactive hyperemia in mice was reversed by the soluble epoxide hydrolase inhibitor ( t -AUCB): Role of adenosine A 2A receptor and plasma oxylipins

Abstract

Coronary reactive hyperemia (CRH) protects the heart against ischemia. Adenosine A2AAR– deficient (A2AAR−/−) mice have increased expression of soluble epoxide hydrolase (sEH); the enzyme responsible for breaking down the cardioprotective epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs). she–inhibition enhances CRH, increases EETs, and modulates oxylipin profiles. We investigated the changes of oxylipins and their impact on CRH in A2AAR−/− and wild type (WT) mice. We hypothesized that the attenuated CRH in A2AAR−/− mice is mediated by changes in oxylipin profiles, and that it can be reversed by either sEH– or ω -hydroxylases–inhibition. Compared to WT mice, A2AAR−/− mice had attenuated CRH and changed oxylipin profiles, which were consistent between plasma and heart perfusate samples, including decreased EET/DHET ratios, and increased hydroxyeicosatetraenoic acids (HETEs). Plasma oxylipns in A2AAR−/− mice indicated an increased proinflammatory state including increased ω-terminal HETEs, decreased epoxyoctadecaenoic / dihydroxyoctadecaenoic acids (EpOMEs/DiHOMEs) ratios, increased 9-hydroxyoctadecadienoic acid, and increased prostanoids. Inhibition of either sEH or ω-hydroxylases reversed the reduced CRH in A2AAR−/− mice. In WT and sEH −/− mice, blocking A2AAR decreased CRH. These data demonstrate that A2AAR–deletion was associated with changes in oxylipin profiles, which may contribute to the attenuated CRH. Also, inhibition of sEH and ω-hydroxylases reversed the reduction in CRH.

Role of oxylipins in cardiovascular diseases

“…Further, the up-regulation of angiotensin II is directly proportional to sEH up-regulation [112] , whereas, sEH inhibition blocks Angiotensin II-induced hypertension in rats [113] . As we mentioned earlier, the plasma levels of both EETs (oxylipins) and DHETs (oxylipins) levels in A2AAR −/− vs A2AAR +/+ mice supported the fi ndings of the heart perfusate samples (cardiac oxylipins) of A2AAR −/− vs A2AAR +/+ mice; EETs/DHETs ratio was decreased by the elevated DHET levels which leads to significant reduction in coronary reactive hyperemic response in A2AAR −/− vs A2AAR +/+ mice [8] .…”

“…The heart perfusate data have demonstrated positive/negative effects of a brief ischemia on cardiac oxylipin levels (local) with enhanced or reduced coronary reactive hyperemic responses depending upon the mice (A2AAR −/− , sEH −/− , Tie2-sEH Tr, CYP2J2 Tr, C57Bl/6, and sEH-inhibitor-treated C57Bl/6 and other transgenic mice), as they are assessed before and after the ischemia in vitro mouse model of isolated heart [9][10][11][12] . Also, blood plasma oxylipins pro-fi le data of A2AAR −/− vs A2AAR +/+ have supported the data of heart perfusates (cardiac oxylipins profi le) of A2AAR −/− vs A2AAR +/+ mice [8] . Further, there are evidences that show a relationship exists between endothelial dysfunctions involving cardiovascular diseases/hypertension and genetic polymorphisms in A2AAR, CYP2J2 and sEH genes in humans [44,[104][105][106][107][108] .…”

“…Oxylipins regulate inflammation, vascular response and coronary hyperemic response [3][4][5][6][7][9][10][11][12] . Recently, in our laboratory, oxylipins were analyzed in both blood plasma and heart perfusates of adenosine A2A receptor knockout (A2AAR −/− ) mice, where soluble epoxide hydrolase (sEH) was overexpressed and CYP2C was underexpressed [69,103] compared to its wild-type mice (A2AAR +/+ ); Tie2-sEH Tr (sEH-overexpressed mice) compared to C57Bl/6; sEH knockout (sEH −/− ) mice compared to its wild-type mice (sEH +/+ ); Tie2-CYP2J2 Tr (CYP2J2-overexpressed) compared to C57Bl/6 mice, and trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid (t-AUCB, sEH-inhibitor) treated C57Bl/6 compared to non-treated C57Bl/6 mice [8][9][10][11][12] . The heart perfusate data have demonstrated positive/negative effects of a brief ischemia on cardiac oxylipin levels (local) with enhanced or reduced coronary reactive hyperemic responses depending upon the mice (A2AAR −/− , sEH −/− , Tie2-sEH Tr, CYP2J2 Tr, C57Bl/6, and sEH-inhibitor-treated C57Bl/6 and other transgenic mice), as they are assessed before and after the ischemia in vitro mouse model of isolated heart [9][10][11][12] .…”

“…and therapies are required to decrease the CVDs. Oxylipins are the oxygenated polyunsaturated fatty acids that regulate infl ammation, vascular response and coronary hyperemic response [3][4][5][6][7][8][9][10][11][12] .…”

Cyp2j5-Gene Deletion Affects on Acetylcholine and Adenosine-Induced Relaxation in Mice: Role of Angiotensin-II and CYP-Epoxygenase Inhibitor

“…In addition, adenosine A 2A receptor (A 2A AR) knockout mice had lower expression of CYP-epoxygenases and higher expression of w-hydroxylases with enhanced NECA (adenosine agonist) and CGS 21680 (A 2A AR-agonist)-induced vasoconstriction (aortic) compared to their respective wild-type mice (Nayeem et al, 2008;Pradhan et al, 2014;Pradhan et al, 2015). Further, Hanif et al recently reported that A 2A AR −/− mice had less plasma EETs compared to wild-type counterparts with reduced coronary reactive hyperemic response (Hanif et al, 2017a). An increase in blood pressure has been reported with enhanced renal vasoconstriction with angiotensin II in female Cyp2j5 −/− compared to female wildtype mice (Athirakul et al, 2008).…”