title: Role of phosphatase activity of soluble epoxide hydrolase in regulating simvastatin-activated endothelial nitric oxide synthase.
abstract: Soluble epoxide hydrolase (sEH) has C-terminal epoxide hydrolase and N-terminal lipid phosphatase activity. Its hydrolase activity is associated with endothelial nitric oxide synthase (eNOS) dysfunction. However, little is known about the role of sEH phosphatase in regulating eNOS activity. Simvastatin, a clinical lipid-lowering drug, also has a pleiotropic effect on eNOS activation. However, whether sEH phosphatase is involved in simvastatin-activated eNOS activity remains elusive. We investigated the role of sEH phosphatase activity in simvastatin-mediated activation of eNOS in endothelial cells (ECs). Simvastain increased the phosphatase activity of sEH, which was diminished by pharmacological inhibitors of sEH phosphatase. In addition, pharmacological inhibition of sEH phosphatase or overexpressing the inactive phosphatase domain of sEH enhanced simvastatin-induced NO bioavailability, tube formation and phosphorylation of eNOS, Akt, and AMP-activated protein kinase (AMPK). In contrast, overexpressing the phosphatase domain of sEH limited the simvastatin-increased NO biosynthesis and eNOS phosphorylation at Ser1179. Simvastatin evoked epidermal growth factor receptor-c-Src-increased Tyr phosphorylation of sEH and formation of an sEH-Akt-AMPK-eNOS complex, which was abolished by the c-Src kinase inhibitor PP1 or c-Src dominant-negative mutant K298M. These findings suggest that sEH phosphatase activity negatively regulates simvastatin-activated eNOS by impeding the Akt-AMPK-eNOS signaling cascade.
authors: Department of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Internal Medicine; National Taiwan University; Taiwan.
authors: Hsin-Han
authors: HH
authors: Hou
authors: School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan.
authors: Yi-Jen
authors: YJ
authors: Liao
authors: Department of Surgery, Zhongxiao Taipei City Hospital, Taipei, Taiwan.
authors: Sheng-Huang
authors: SH
authors: Hsiao
authors: Cardiovascular Division, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors: Song-Kun
authors: SK
authors: Shyue
authors: Department of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Genome Research Center, National Yang-Ming University, Taipei, Taiwan.
authors: Tzong-Shyuan
authors: TS
authors: Lee
mesh_terms: D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D004851:Epoxide Hydrolases / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D019821:Simvastatin / Q000008:administration & dosage*; D012995:Solubility
chemical_list: D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III; D010744:Phosphoric Monoester Hydrolases; D004851:Epoxide Hydrolases