1. The serum- and glucocorticoid-inducible kinase Sgk-1 is involved in pulmonary vascular remodeling: role in redox-sensitive regulation of tissue factor by thrombin.
- Author
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BelAiba RS, Djordjevic T, Bonello S, Artunc F, Lang F, Hess J, and Görlach A
- Subjects
- 3-Phosphoinositide-Dependent Protein Kinases, Animals, Cells, Cultured, Humans, Hypertension, Pulmonary etiology, Hypertension, Pulmonary pathology, Immediate-Early Proteins genetics, Mice, Mice, Knockout, Muscle, Smooth, Vascular pathology, NADPH Oxidases physiology, NF-kappa B physiology, Oxidation-Reduction, Phosphatidylinositol 3-Kinases physiology, Protein Serine-Threonine Kinases genetics, Reactive Oxygen Species, p38 Mitogen-Activated Protein Kinases physiology, Immediate-Early Proteins physiology, Protein Serine-Threonine Kinases physiology, Pulmonary Artery pathology, Thrombin pharmacology, Thromboplastin genetics
- Abstract
The stress-responsive serum- and glucocorticoid-inducible kinase Sgk-1 is involved in osmoregulation and cell survival and may contribute to fibrosis and hypertension. However, the function of Sgk-1 in vascular remodeling and thrombosis, 2 major determinants of pulmonary hypertension (PH), has not been elucidated. We investigated the role of Sgk-1 in thrombin signaling and tissue factor (TF) expression and activity in pulmonary artery smooth muscle cells (PASMC). Thrombin increased Sgk-1 activity and mRNA and protein expression. H2O2 similarly induced Sgk-1 expression. Antioxidants, dominant-negative Rac, and depletion of the NADPH oxidase subunit p22phox diminished thrombin-induced Sgk-1 expression. Inhibition of p38 mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and phosphoinositide-dependent kinase-1 prevented thrombin-induced Sgk-1 expression. Thrombin or Sgk-1 overexpression enhanced TF expression and procoagulant activity, whereas TF upregulation by thrombin was diminished by kinase-deficient Sgk-1 and was not detectable in fibroblasts from mice deficient in sgk-1 (sgk1(-/-)). Similarly, dexamethasone treatment failed to induce TF expression and activity in lung tissue from sgk1(-/-) mice. Transcriptional induction of TF by Sgk-1 was mediated through nuclear factor kappaB. Finally, Sgk-1 and TF proteins were detected in the media of remodeled pulmonary vessels associated with PH. These data show that thrombin potently induces Sgk-1 involving NADPH oxidases, phosphatidylinositol 3-kinase, p38 mitogen-activated protein kinase, and phosphoinositide-dependent kinase-1, and that activation of nuclear factor kappaB by Sgk-1 mediates TF expression and activity by thrombin. Because enhanced procoagulant activity can promote pulmonary vascular remodeling, and Sgk-1 and TF were present in the media of remodeled pulmonary vessels, this pathway may play a critical role in vascular remodeling in PH.
- Published
- 2006
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