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(Circulation Research. 2006;98:828.)
© 2006 American Heart Association, Inc.

Integrative Physiology

The Serum- and Glucocorticoid-Inducible Kinase Sgk-1 Is Involved in Pulmonary Vascular Remodeling

Role in Redox-Sensitive Regulation of Tissue Factor by Thrombin

Rachida S. BelAiba, Talija Djordjevic, Steve Bonello, Ferruh Artunc, Florian Lang, John Hess, Agnes Görlach

From the Experimental Pediatric Cardiology (R.S.B., T.D., S.B., J.H., A.G.), Department of Pediatric Cardiology and Congenital Heart Disease, German Heart Center Munich at the Technical University Munich; and Institute for Physiology I (F.A., F.L.), University of Tuebingen, Germany.

Correspondence to Agnes Görlach, MD, Experimental Pediatric Cardiology, Department of Pediatric Cardiology and Congenital Heart Disease, German Heart Center Munich at the Technical University Munich, Lazarettstr. 36, D-80636 München, Germany. E-mail goerlach{at}dhm.mhn.de

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 B. 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 B 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.

Key Words: sgk-1 • thrombin • tissue factor • NADPH oxidase • coagulant activity • pulmonary vascular remodeling • pulmonary artery smooth muscle cells • nuclear factor B

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