Agba Stephanie, Hanif Ahmad, Edin Matthew L, Zeldin Darryl C, Nayeem Mohammed A
Pharmaceutical Sciences, School of Pharmacy, Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, WV, United States.
Division of Intramural Research, NIEHS/NIH, Durham, NC, United States.
Front Pharmacol. 2020 Feb 5;11:27. doi: 10.3389/fphar.2020.00027. eCollection 2020.
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 A receptor-induced enhance relaxation, but we did not see the response in CYP2J-epoxygenase knockout mice. Therefore, we hypothesized that -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 -(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH, CYP-epoxygenase inhibitor; 10M) and Ang-II (10M). In mice, ACh-induced relaxation was different from C57Bl/6 mice, at 10 M (76.1 ± 3.3 58.3 ± 5.2, < 0.05). However, ACh-induced relaxation was not blocked by MS-PPOH in : 58.5 ± 5.0%, > 0.05, but blocked in C57Bl/6: 52.3 ± 7.5%, < 0.05, and Ang-II reduces ACh-induced relaxation in both and C57Bl/6 mice (38.8 ± 3.9% and 45.9 ± 7.8, 0.05). In addition, NECA-induced response was tested with Ang-II. In mice, NECA-induced response was not different from C57Bl/6 mice at 10M (23.1 ± 2.1 21.1 ± 3.8, > 0.05). However, NECA-induced response was reduced by Ang-II in both and C57Bl/6 mice (-10.8 ± 2.3% and 3.2 ± 2.7, 0.05). Data suggest that ACh-induced relaxation in mice depends on nitric oxide (NO) but not CYP-epoxygenases, and the NECA-induced different response in male female mice when Ang-II treated.
此前，我们发现人CYP2J2在血管内皮中的过表达增强了Tie2-CYP2J2 Tr小鼠的冠状动脉反应性充血，并且eNOS小鼠中CYP2J-环氧化酶过表达，伴随腺苷A受体诱导的舒张增强，但我们在CYP2J-环氧化酶基因敲除小鼠中未观察到这种反应。因此，我们推测基因缺失会影响乙酰胆碱和5'-N-乙基甲酰胺基腺苷（NECA）（腺苷）诱导的舒张，并且在小鼠中它们的反应会被血管紧张素-II（Ang-II）部分抑制。用（甲基磺酰基）-2-（2-丙炔氧基）-苯己酰胺（MS-PPOH，CYP-环氧化酶抑制剂；10μM）和Ang-II（10μM）检测乙酰胆碱（Ach）诱导的反应。在小鼠中，10μM时Ach诱导的舒张与C57Bl/6小鼠不同（76.1±3.3对58.3±5.2，P<0.05）。然而，在小鼠中MS-PPOH并未阻断Ach诱导的舒张：58.5±5.0%，P>0.05，但在C57Bl/6小鼠中被阻断：52.3±7.5%，P<0.05，并且Ang-II降低了小鼠和C57Bl/6小鼠中Ach诱导的舒张（38.8±3.9%和45.9±7.8，P<0.05）。此外，用Ang-II检测NECA诱导的反应。在小鼠中，10μM时NECA诱导的反应与C57Bl/6小鼠无差异（23.1±2.1对21.1±3.8，P>0.05）。然而，在小鼠和C-57Bl/6小鼠中Ang-II均降低了NECA诱导的反应（-10.8±2.3%和-3.2±2.7，P<0.05）。数据表明，小鼠中Ach诱导的舒张依赖于一氧化氮（NO）而非CYP-环氧化酶，并且在Ang-II处理时，NECA诱导的反应在雄性和雌性小鼠中存在差异。
