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.

Deletion or inhibition of soluble epoxide hydrolase protects against brain damage and reduces microglia-mediated neuroinflammation in traumatic brain injury

“…However, the phosphatase activity of sEH may also be involved in the pathogenesis of TBI. The phosphatase domain of sEH has been shown to negatively regulate VEGF-mediated endothelial NOS (eNOS) activity in vivo [ 61 ] and Akt-AMPK-mediated eNOS in vitro [ 62 ]. Since eNOS activity is implicated in mechanisms of neuronal injury and cerebral blood flow changes following brain injury [ 63 ], the sEH phosphatase activity may also participate in the pathogenesis of TBI.…”

Renal Ischemia/Reperfusion Injury in Soluble Epoxide Hydrolase-Deficient Mice

“…Accordingly, differences observed comparing the effects of sEH deletion and sEH inhibition may indicate an important role of the N-terminal phosphatase domain in the given disease model as discussed for hypoxia-induced pulmonary hypertension [ 53 ]. The function of the phosphatase domain is only partially understood [ 29 ]; however, recent findings suggest that the N-terminal domain is involved in regulating the phosphorylation state and activity of endothelial nitric oxide synthase [ 54 , 55 ].…”

Soluble Epoxide Hydrolase and Brain Cholesterol Metabolism

“…The phosphatase activity of sEH downregulates activated eNOS signaling and NO production. Inhibition of sEH phosphatase activity was shown to increase NO production and prolong the phosphorylation of eNOS (Hou et al, 2011;Hou et al, 2015). In the nervous system, NO has both physiological and pathological functions.…”