Abstract:
RATIONALE:Activation of Nox1 initiates redox-dependent signaling events crucial in the pathogenesis of vascular disease. Selective targeting of Nox1 is an attractive potential therapy, but requires a better understanding of the molecular modifications controlling its activation. OBJECTIVE:To determine whether posttranslational modifications of Nox1 regulate its activity in vascular cells. METHODS AND RESULTS:We first found evidence that Nox1 is phosphorylated in multiple models of vascular disease. Next, studies using mass spectroscopy and a pharmacological inhibitor demonstrated that protein kinase C-beta1 mediates phosphorylation of Nox1 in response to tumor necrosis factor-α. siRNA-mediated silencing of protein kinase C-beta1 abolished tumor necrosis factor-α-mediated reactive oxygen species production and vascular smooth muscle cell migration. Site-directed mutagenesis and isothermal titration calorimetry indicated that protein kinase C-beta1 phosphorylates Nox1 at threonine 429. Moreover, Nox1 threonine 429 phosphorylation facilitated the association of Nox1 with the NoxA1 activation domain and was necessary for NADPH oxidase complex assembly, reactive oxygen species production, and vascular smooth muscle cell migration. CONCLUSIONS:We conclude that protein kinase C-beta1 phosphorylation of threonine 429 regulates activation of Nox1 NADPH oxidase.
journal_name
Circ Resjournal_title
Circulation researchauthors
Streeter J,Schickling BM,Jiang S,Stanic B,Thiel WH,Gakhar L,Houtman JC,Miller FJ Jrdoi
10.1161/CIRCRESAHA.115.304267subject
Has Abstractpub_date
2014-11-07 00:00:00pages
911-8issue
11eissn
0009-7330issn
1524-4571pii
CIRCRESAHA.115.304267journal_volume
115pub_type
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