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Effects of epoxyeicosatrienoic acids on levels of eNOS phosphorylation and relevant signaling transduction pathways involved

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Science China(Life Sciences) 2005年第5期48卷 495-505页

作者： CHEN Ruijuan1, JIANG Jiangang1, XIAO Xiao2 & WANG Daowen1 1. The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China 2. Departments of Molecular Genetics and Biochemistry & Gene Therapy Center, University of Pittsburgh, Pittsburgh, PA, USA The Institute of Hypertension and Department of Internal Medicine Tongji Hospital Tongji Medical College Huazhong University of Science & Technology Wuhan 430030 China Departments of Molecular Genetics and Biochemistry & Gene Therapy Center University of Pittsburgh Pittsburgh PA USA

Endothelial nitric oxide synthase (eNOS) is a key enzyme responsible for the regu-lation of vascular homeostasis. Many humor factors and mechanical forces can affect eNOS ac-tivity via phosphorylation modification but the mechanisms involved vary with stimuli applied. We have demonstrated that cytochrome P450 (CYP) epoxygenase-dependent metabolites of ara-chidonic acid, epoxyeicosatrienoic acids (EETs), can robustly up-regulate eNOS expression and its activity, however the relevant signaling pathways responsible for activity regulation are not well known. In this study, we explored the role of PI3 kinase (PI3K)/protein kinase B (Akt) sig-naling pathway in eNOS expression and its phosphorylation in response to EETs via direct addi-tion of EETs into cultured bovine aorta endothelial cells (BAECs) and recombinant adeno- asso-ciated virus-mediated transfection of CYP epoxygenase genes CYPF87V and CYP2C11 to pro-duce endogenous EETs followed by co-treatment with PI3K or Akt inhibitor. Results show that both exogenous and endogenous EETs could remarkably enhance eNOS expression and its phosphorylation at Ser1179 and Thr497 residues; PI3K inhibitor LY294002 could inhibit EETs-induced increase in eNOS-Ser(P)1179 but had no effect on the change of eNOS-Thr(P)497, while Akt inhibitor could attenuate the increase in phosphor-eNOS at both residues; both of the two inhibitors could block EETs-enhanced eNOS expression. These results lead to conclusions: (i) EETs-mediated regulation of eNOS activity may be related with the changes of phosphoryla-tion level at eNOS-Ser1179 via PI3K/Akt and eNOS-Thr497 via Akt; (ii) PI3K/Akt signaling pathway is involved in the up-regulation of eNOS expression by EETs.

关键词： epoxyeicosatrienoic acids, endothelial nitric oxide synthase (eNOS), PI3 kinase, Protein kinase B (Akt), phosphorylation.

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Vitamin C activation of the biosynthesis of epoxyeicosatrienoic acids

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Advances in Bioscience and Biotechnology 2012年第3期3卷 204-218页

作者： Houli Jiang Fiona E. Harrison Kavita Jain Samantha Benjamin James M. May Joan P. Graves Darryl C. Zeldin John R. Falck Bruce D. Hammock John C. McGiff Department of Biochemistry University of Texas Southwestern Medical Center Dallas Texas USA Department of Medicine Vanderbilt University Nashville Tennessee USA Department of Pharmacology New York Medical College Valhalla New York USA Entomology and Cancer Center University of California Davis California USA NIH/NIEHS Research Triangle Park North Carolina USA

The cardiovascular effects of vitamin C (VitC) could be mediated by epoxyeicosatrienoic acids (EETs). We aimed to study the mechanism of VitC-dependent microsomal formation of cis- and trans-EETs and the regulation of EET levels in rat isolated perfused kidneys and in vivo. VitC biphasically stimulated rat kidney microsomal cis- and trans-EET formation in a ratio of 1:2, involving the participation of lipid hydroperoxides (LOOHs), Fe2+ , and cytochrome P450 (CYP). Levels of LOOHs correlated with microsomal EET production. LOOH stimulation of CYP isoforms resulted in preferred trans- over cis-EET formation from arachidonic acid and was associated with the cleavage of LOOHs, which indicated a CYP peroxy-genase activity. EETs contributed to VitC-induced vasodilator responses in rat isolated perfused kidneys. VitC (1 mg/ml) given in the drinking water for 9 days doubled rat urinary EET excretion, increased plasma levels of EETs, mostly trans-EETs, by 40%, and reduced plasma levels of 20-hydroxyeicosatetraenoic acid. Depletion of VitC in brain cortex and kidney tissues by more than 20- and 50-fold, respectively, in gulonolactone oxidase-knockout mice was associated with mild increases in tissue EETs. These data suggest that LOOHs are a determinant factor for EET formation in vivo in which VitC exerts a key regulatory effect. VitC-activated CYP peroxygenase activity may represent a CYP interaction with lipoxygenases and cyclooxygenases to mediate the cardiovascular effects of VitC via formation of EETs.

关键词： Vitamin C epoxyeicosatrienoic Acids Cytochrome P450 Lipid Hydroperoxides Peroxygenase

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Endothelium-derived hyperpolarizing factor and diabetes

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World Journal of Cardiology 2011年第1期3卷 25-31页

作者： Luis A Martinez-Lemus Department of Medical Pharmacology and Physiology and Internal Medicine Dalton Cardiovascular Research Center University of Missouri-Columbia Columbia MO 65211 United States

In addition to its role as a barrier between blood and tissues, the vascular endothelium is responsible for the synthesis and released of a number of vasodilators including prostaglandins, nitric oxide and endotheliumderived hyperpolarizing factor (EDHF). As one of these vasodilators, the specific nature of EDHF has not been fully elucidated, although a number of roles have been proposed. Importantly, many conditions, such as hypertension, hyperlipidemia, heart failure, ischemiareperfusion and diabetes mellitus comprise vascular endothelial dysfunction with EDHF dysregulation. This article reviews reports on the role of EDHF in diabetesrelated endothelial dysfunction.

关键词： Endothelial-dysfunction Hyperglycemia Potassium channels epoxyeicosatrienoic acids Hydrogen peroxide

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