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

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 &kgr;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 &kgr;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.

[1]  Jiahuai Han,et al.  IL-6 activates serum and glucocorticoid kinase via p38alpha mitogen-activated protein kinase pathway. , 2005, American journal of physiology. Cell physiology.

[2]  T. Kietzmann,et al.  Thrombin activates the p21-activated kinase in pulmonary artery smooth muscle cells , 2005, Thrombosis and Haemostasis.

[3]  L. Klotz,et al.  Phosphoinositide 3-kinase signaling in the cellular response to oxidative stress , 2005, Biological chemistry.

[4]  Xiaodong Cheng,et al.  Antiapoptotic effect of serum and glucocorticoid-inducible protein kinase is mediated by novel mechanism activating I{kappa}B kinase. , 2005, Cancer research.

[5]  A. Görlach,et al.  Insights into the redox control of blood coagulation: role of vascular NADPH oxidase-derived reactive oxygen species in the thrombogenic cycle. , 2004, Antioxidants & redox signaling.

[6]  A. Görlach,et al.  Rac regulates thrombin-induced tissue factor expression in pulmonary artery smooth muscle cells involving the nuclear factor-kappaB pathway. , 2004, Antioxidants & redox signaling.

[7]  N. Mackman,et al.  Dexamethasone enhances LPS induction of tissue factor expression in human monocytic cells by increasing tissue factor mRNA stability , 2004, Journal of leukocyte biology.

[8]  M. Humbert,et al.  Cellular and molecular pathobiology of pulmonary arterial hypertension. , 2004, Journal of the American College of Cardiology.

[9]  G. Firestone,et al.  Stimulus-Dependent Regulation of Serum and Glucocorticoid Inducible Protein Kinase (SGK) Transcription, Subcellular Localization and Enzymatic Activity , 2003, Cellular Physiology and Biochemistry.

[10]  A. C. Maiyar,et al.  Expression of the Serum- and Glucocorticoid-inducible Protein Kinase, Sgk, Is a Cell Survival Response to Multiple Types of Environmental Stress Stimuli in Mammary Epithelial Cells* , 2003, The Journal of Biological Chemistry.

[11]  K. Mann,et al.  Thrombin formation. , 2003, Chest.

[12]  T. Risler,et al.  Up-Regulation of the Human Serum and Glucocorticoid-Dependent Kinase 1 in Glomerulonephritis , 2002, Kidney and Blood Pressure Research.

[13]  K. Klingel,et al.  Impaired renal Na(+) retention in the sgk1-knockout mouse. , 2002, The Journal of clinical investigation.

[14]  Arya M. Sharma,et al.  Serum- and Glucocorticoid-Regulated Kinase (SGK1) Gene and Blood Pressure , 2002, Hypertension.

[15]  S. Beebe,et al.  Differential transcriptional regulation by the alpha- and gamma-catalytic subunit isoforms of cAMP-dependent protein kinase. , 2002, Archives of biochemistry and biophysics.

[16]  E. Schleicher,et al.  Excessive Transcription of the Human Serum and Glucocorticoid Dependent Kinase hSGK1 in Lung Fibrosis , 2002, Cellular Physiology and Biochemistry.

[17]  C. Shelly,et al.  Activation of SGK1 by HGF, Rac1 and integrin-mediated cell adhesion in MDCK cells: PI-3K-dependent and -independent pathways. , 2002, Journal of cell science.

[18]  R. Busse,et al.  NADPH Oxidase Mediates Tissue Factor–Dependent Surface Procoagulant Activity by Thrombin in Human Vascular Smooth Muscle Cells , 2002, Circulation.

[19]  T. Lüscher,et al.  Statin Prevents Tissue Factor Expression in Human Endothelial Cells: Role of Rho/Rho-Kinase and Akt Pathways , 2002, Circulation.

[20]  S. Bröer,et al.  Expression of the Serine/Threonine Kinase hSGK1 in Chronic Viral Hepatitis , 2002, Cellular Physiology and Biochemistry.

[21]  S. Beebe,et al.  Differential transcriptional regulation by the alpha- and gamma-catalytic subunit isoforms of cAMP-dependent protein kinase. , 2002, Archives of biochemistry and biophysics.

[22]  P. Cohen,et al.  Regulation and Physiological Roles of Serum- and Glucocorticoid-Induced Protein Kinase Isoforms , 2001, Science's STKE.

[23]  R. Busse,et al.  Thrombin Activates the Hypoxia-Inducible Factor-1 Signaling Pathway in Vascular Smooth Muscle Cells: Role of the p22phox-Containing NADPH Oxidase , 2001, Circulation research.

[24]  R. Simari,et al.  Role for Tissue Factor Pathway in Murine Model of Vascular Remodeling , 2001, Circulation research.

[25]  K. Nguyen,et al.  Thrombin-induced MCP-1 Expression Involves Activation of the p22phox-containing NADPH Oxidase in Human Vascular Smooth Muscle Cells , 2001, Thrombosis and Haemostasis.

[26]  E. Lein,et al.  Tissue-specific expression of the transcriptionally regulated serum and glucocorticoid-inducible protein kinase (Sgk) during mouse embryogenesis , 2001, Mechanisms of Development.

[27]  E. Nishida,et al.  The ERK MAP kinase pathway mediates induction of SGK (serum‐ and glucocorticoid‐inducible kinase) by growth factors , 2001, Genes to cells : devoted to molecular & cellular mechanisms.

[28]  A. So,et al.  Enhanced expression of genes involved in coagulation and fibrinolysis in murine arthritis , 2000, Arthritis Research & Therapy.

[29]  G. Firestone,et al.  Hyperosmotic Stress Stimulates Promoter Activity and Regulates Cellular Utilization of the Serum- and Glucocorticoid-inducible Protein Kinase (Sgk) by a p38 MAPK-dependent Pathway* , 2000, The Journal of Biological Chemistry.

[30]  S. Decker,et al.  Oxidative stress and vanadate induce tyrosine phosphorylation of phosphoinositide-dependent kinase 1 (PDK1). , 2000, Biochemistry.

[31]  J. M. Kumar,et al.  Sgk, a putative serine/threonine kinase, is differentially expressed in the kidney of diabetic mice and humans. , 1999, Journal of the American Society of Nephrology : JASN.

[32]  C. Kanthou,et al.  Thrombin activates transcription factors sp1, NF-kappaB, and CREB: importance of the use of phosphatase inhibitors during nuclear protein extraction for the assessment of transcription factor DNA-binding activities. , 1999, Analytical biochemistry.

[33]  A. C. Maiyar,et al.  Serum and glucocorticoid‐inducible kinase (SGK) is a target of the PI 3‐kinase‐stimulated signaling pathway , 1999, The EMBO journal.

[34]  P. Cohen,et al.  Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. , 1999, The Biochemical journal.

[35]  L. Delmolino,et al.  Heparin suppresses sgk, an early response gene in proliferating vascular smooth muscle cells , 1997, Journal of cellular physiology.

[36]  F. Lang,et al.  Cloning and characterization of a putative human serine/threonine protein kinase transcriptionally modified during anisotonic and isotonic alterations of cell volume. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[37]  A. Chaouat,et al.  The role of thrombosis in severe pulmonary hypertension. , 1996, The European respiratory journal.

[38]  A. C. Maiyar,et al.  Characterization of sgk, a novel member of the serine/threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum , 1993, Molecular and cellular biology.