Regulation of endothelial nitric-oxide synthase activity through phosphorylation in response to epoxyeicosatrienoic acids
| Autor: | Jia ning Wang, Yong Wang, L. Ashley Cowart, Bin Xiao, Yong Xia, Rui Juan Chen, Dao Wen Wang, Jian Gang Jiang, Xiao Xiao, Shilin Yang |
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| Rok vydání: | 2007 |
| Předmět: |
Male
MAPK/ERK pathway Epoxygenase Nitric Oxide Synthase Type III MAP Kinase Signaling System Physiology Morpholines Aorta Thoracic Cytochrome P-450 CYP2J2 Biochemistry CYP2J2 8 11 14-Eicosatrienoic Acid Cytochrome P-450 Enzyme System Enos Serine Animals Amino Acid Sequence Apigenin Phosphorylation Protein kinase A Protein kinase B Cells Cultured Phosphoinositide-3 Kinase Inhibitors Flavonoids Pharmacology biology Kinase Chemistry Cell Biology biology.organism_classification Rats Cell biology Phosphothreonine Chromones Oxygenases cardiovascular system biology.protein Epoxy Compounds Cattle lipids (amino acids peptides and proteins) Proto-Oncogene Proteins c-akt Inositol |
| Zdroj: | Prostaglandins & Other Lipid Mediators. 82:162-174 |
| ISSN: | 1098-8823 |
| Popis: | Endothelial nitric oxide synthase (eNOS) is a key enzyme in NO-mediated cardiovascular homeostasis and its activity is modulated by a variety of hormonal and mechanical stimuli via phosphorylation modification. Our previous study has demonstrated that epoxyeicosatrienoic acids (EETs), the cytochrome P450 (CYP)-dependent metabolites of arachidonic acid, could robustly up-regulate eNOS expression. However, the molecular mechanism underlying the effects of EETs on eNOS remains elusive. Particularly, whether and how EETs affect eNOS phosphorylation is unknown. In the present study, we investigated the effects of EETs on eNOS phosphorylation with cultured bovine aortic endothelial cells (BAECs). BAECs were either treated with exogenous EETs or infected with recombinant adeno-associated virus (rAAV) carrying CYP2C11-CYPOR, CYP102 F87V mutant and CYP2J2, respectively, to increase endogenous EETs. Both addition of EETs and CYP epoxygenase transfection markedly increased eNOS phosphorylation at its Ser1179 and Thr497 residues. Inhibition of phosphatidylinositol 3-kinase (PI3K) with LY294002 prevented EETs-induced increases of eNOS-Ser(P)1179 but had no effect on the phosphorylation status of Thr497. However, inhibitors of protein kinase B (Akt), mitogen-activated protein kinase (MAPK) and MAPK kinase could block phosphorylation of eNOS at both sites. Inhibition of these kinases also attenuated the up-regulation of eNOS expression by EETs. Finally, administration of viral CYP epoxygenases expression vectors into rats enhanced eNOS phosphorylation and function in vivo. Thus, in addition to up-regulating eNOS expression, EETs also augment eNOS function by enhancing eNOS phosphorylation. EETs-induced up-regulation of eNOS phosphorylation and expression appears to involve in both PI3K/Akt and MAPK pathways. |
| Databáze: | OpenAIRE |
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