The Serum- and Glucocorticoid-Inducible Kinase Sgk-1 Is Involved in Pulmonary Vascular Remodeling: Role in Redox-Sensitive Regulation of Tissue Factor by Thrombin

• Published in: Circulation research 2006-03, Vol.98 (6), p.828-836
• Main Authors: BelAiba, Rachida S, Djordjevic, Talija, Bonello, Steve, Artunc, Ferruh, Lang, Florian, Hess, John, Görlach, Agnes
• Format: Article
• Language: English
• Subjects: 3-Phosphoinositide-Dependent Protein Kinases; Animals; Biological and medical sciences; Cells, Cultured; Fundamental and applied biological sciences. Psychology; Humans; Hypertension, Pulmonary - etiology; Hypertension, Pulmonary - pathology; Immediate-Early Proteins - genetics; Immediate-Early Proteins - physiology; Mice; Mice, Knockout; Muscle, Smooth, Vascular - pathology; NADPH Oxidases - physiology; NF-kappa B - physiology; Oxidation-Reduction; p38 Mitogen-Activated Protein Kinases - physiology; Phosphatidylinositol 3-Kinases - physiology; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - physiology; Pulmonary Artery - pathology; Reactive Oxygen Species; Thrombin - pharmacology; Thromboplastin - genetics; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000210539.54861.27

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 κB. 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 κB 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.