Abstract
Previously, we showed vascular endothelial overexpression of human-CYP2J2 enhances coronary reactive hyperemia in Tie2-CYP2J2 Tr mice, and eNOS−/− mice had overexpression of CYP2J-epoxygenase with adenosine A2A receptor-induced enhance relaxation, but we did not see the response in CYP2J-epoxygenase knockout mice. Therefore, we hypothesized that Cyp2j5-gene deletion affects acetylcholine- and 5'-N-ethylcarboxamidoadenosine (NECA) (adenosine)-induced relaxation and their response is partially inhibited by angiotensin-II (Ang-II) in mice. Acetylcholine (Ach)-induced response was tested with N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH, CYP-epoxygenase inhibitor; 10−5M) and Ang-II (10−6M). In Cyp2j5−/− mice, ACh-induced relaxation was different from C57Bl/6 mice, at 10−5 M (76.1 ± 3.3 vs. 58.3 ± 5.2, P < 0.05). However, ACh-induced relaxation was not blocked by MS-PPOH in Cyp2j5−/−: 58.5 ± 5.0%, P > 0.05, but blocked in C57Bl/6: 52.3 ± 7.5%, P < 0.05, and Ang-II reduces ACh-induced relaxation in both Cyp2j5−/− and C57Bl/6 mice (38.8 ± 3.9% and 45.9 ± 7.8, P <0.05). In addition, NECA-induced response was tested with Ang-II. In Cyp2j5−/− mice, NECA-induced response was not different from C57Bl/6 mice at 10−5M (23.1 ± 2.1 vs. 21.1 ± 3.8, P > 0.05). However, NECA-induced response was reduced by Ang-II in both Cyp2j5−/− and C57Bl/6 mice (−10.8 ± 2.3% and 3.2 ± 2.7, P < 0.05). Data suggest that ACh-induced relaxation in Cyp2j5−/− mice depends on nitric oxide (NO) but not CYP-epoxygenases, and the NECA-induced different response in male vs. female Cyp2j5−/− mice when Ang-II treated.
Highlights
Arachidonic acid (AA) can be metabolized into epoxyeicosatrienoic acids (EETs) through cytochrome P450 (CYP)-epoxygenases, like CYP2Cs and CYP2Js, and the cytochrome P450 (CYP) whydroxylases (CYP4A, CYP4B, CYP4F, CYP4V, CYP4X, CYP4Z, etc.) hydroxylate AA to HETEs, including 20-HETE which is a potent vasoconstrictor (Hoopes et al, 2015)
We report novel findings regarding the vascular response between Cyp2j5−/− vs. C57Bl/6 mice and their interactions among CYP-epoxygenase, w-hydroxlase and AngII. (1) Disruption of Cyp2j5 gene in mice (Cyp2j5−/−) reduced ACh-induced concentration-dependent relaxation compared to C57Bl/6 mice
Loss of Cyp2j5 showed reduced ACh-induced relaxation, and Cyp2j5 protein is detected in kidneys/mouse aorta/visceral adipose tissues, and is involved in the conversion of AAs into EETs (Ma et al, 2004; Burgess et al, 2012; Nayeem et al, 2013)
Summary
Arachidonic acid (AA) can be metabolized into epoxyeicosatrienoic acids (EETs) through cytochrome P450 (CYP)-epoxygenases, like CYP2Cs and CYP2Js, and the cytochrome P450 (CYP) whydroxylases (CYP4A, CYP4B, CYP4F, CYP4V, CYP4X, CYP4Z, etc.) hydroxylate AA to HETEs (hydroxyeicosatetraenoic acids), including 20-HETE which is a potent vasoconstrictor (Hoopes et al, 2015). Yang et al, and Hanif et al, reported that an overexpression of CYP2J2 protects vascular endothelium against hypoxia-reoxygenation injury/ischemia/reperfusion injury with enhanced coronary reactive hyperemic (CRH) response in isolated mouse heart model (Yang et al, 2001; Hanif et al, 2017b), and the vascular endothelial CYP2Cs and CYP2Js are the main source of EETs (5,6-, 8,9-, 11,12-, and 14,15-EET regioisomers) generation (Rosolowsky and Campbell, 1996; Fisslthaler et al, 1999; Node et al, 1999). EETs have been observed to produce relaxation in isolated coronary arteries at concentrations as low as 10 pM and are involved in increased CRH response (Fang et al, 2001; Hanif et al, 2016a; Hanif et al, 2016b; Hanif et al, 2017b). The EETinduced relaxation in bovine coronary arteries and mouse aorta is inhibited by the EET antagonist, 14,15-epoxyeicosa-5(Z)-enoic acid (Gauthier et al, 2002; Nayeem et al, 2009; Nayeem et al, 2013; Pradhan et al, 2014)
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