Vanella Luca, Canestraro Martina, Lee Craig R, Cao Jian, Zeldin Darryl C, Schwartzman Michal L, Abraham Nader G
Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA; Department of Drug Sciences, University of Catania, Catania, Italy.
Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
Prostaglandins Other Lipid Mediat. 2015 Jul;120:139-47. doi: 10.1016/j.prostaglandins.2015.04.004. Epub 2015 Apr 20.
Increased CYP epoxygenase activity and consequently up regulation of epoxyeicosatrienoic acids (EETs) levels provides protection against metabolic syndrome and cardiovascular diseases. Conversion of arachidonic acid epoxides to diols by soluble epoxide hydrolase (sEH) diminishes the beneficial cardiovascular properties of these epoxyeicosanoids. We therefore examined the possible biochemical consequences of sEH deletion on vascular responses in male and female mice. Through the use of the sEH KO mouse, we provide evidence of differences in the compensatory response in the balance between nitric oxide (NO), carbon monoxide (CO), EETs and the vasoconstrictor 20-HETE in male and female KO mice. Serum levels of adiponectin, TNFα, IL-1b and MCP1 and protein expression in vascular tissue of p-AMPK, p-AKT and p-eNOS were measured. Deletion of sEH caused a significant (p<0.05) decrease in body weight, and an increase in adiponectin, pAMPK and pAKT levels in female KO mice compared to male KO mice. Gene deletion resulted in a higher production of renal EETs in female KO compared to male KO mice and, concomitantly, we observed an increase in renal 20-HETEs levels and superoxide anion production only in male KO mice. sEH deletion increased p-AKT and p-eNOS protein expression but decreased p-AMPK levels in female KO mice. Increased levels of p-eNOS at Thr-495 were observed only in KO male mice. While p-eNOS at 1177 were not significantly different between male and female. Nitric oxide production was unaltered in male KO mice. These results provide evidence of gender differences in the preservation of vascular homeostasis in response to sEH deletion which involves regulation of phosphorylation of eNOS at the 495 site.
细胞色素P450环氧化酶活性增加以及随之而来的环氧二十碳三烯酸（EETs）水平上调可预防代谢综合征和心血管疾病。可溶性环氧化物水解酶（sEH）将花生四烯酸环氧化物转化为二醇会削弱这些环氧二十碳三烯酸的有益心血管特性。因此，我们研究了sEH基因敲除对雄性和雌性小鼠血管反应可能产生的生化影响。通过使用sEH基因敲除小鼠，我们提供了证据，证明雄性和雌性基因敲除小鼠在一氧化氮（NO）、一氧化碳（CO）、EETs和血管收缩剂20-羟基二十碳四烯酸（20-HETE）之间平衡的代偿反应存在差异。测量了血清脂联素、肿瘤坏死因子α（TNFα）、白细胞介素-1β（IL-1b）和单核细胞趋化蛋白1（MCP1）水平以及血管组织中磷酸化腺苷酸活化蛋白激酶（p-AMPK）、磷酸化蛋白激酶B（p-AKT）和磷酸化内皮型一氧化氮合酶（p-eNOS）的蛋白表达。与雄性基因敲除小鼠相比，sEH基因敲除导致雌性基因敲除小鼠体重显著降低（p<0.05），脂联素、pAMPK和pAKT水平升高。与雄性基因敲除小鼠相比，基因敲除导致雌性基因敲除小鼠肾脏EETs生成增加，同时，我们仅在雄性基因敲除小鼠中观察到肾脏20-HETEs水平和超氧阴离子生成增加。sEH基因敲除增加了雌性基因敲除小鼠中p-AKT和p-eNOS蛋白表达，但降低了p-AMPK水平。仅在基因敲除雄性小鼠中观察到苏氨酸495位点的p-eNOS水平升高。而1177位点的p-eNOS在雄性和雌性之间无显著差异。雄性基因敲除小鼠中的一氧化氮生成未改变。这些结果提供了证据，证明在响应sEH基因敲除时，维持血管稳态存在性别差异，这涉及eNOS在495位点的磷酸化调节。
