BelAiba Rachida S, Djordjevic Talija, Bonello Steve, Artunc Ferruh, Lang Florian, Hess John, Görlach Agnes
Experimental Pediatric Cardiology, Department of Pediatric Cardiology and Congenital Heart Disease, German Heart Center Munich, Technical University Munich, Munich, Germany.
Circ Res. 2006 Mar 31;98(6):828-36. doi: 10.1161/01.RES.0000210539.54861.27. Epub 2006 Feb 16.
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.
应激反应性血清和糖皮质激素诱导激酶Sgk-1参与渗透压调节和细胞存活，并可能导致纤维化和高血压。然而，Sgk-1在血管重塑和血栓形成（肺动脉高压（PH）的两个主要决定因素）中的作用尚未阐明。我们研究了Sgk-1在肺动脉平滑肌细胞（PASMC）中凝血酶信号传导以及组织因子（TF）表达和活性中的作用。凝血酶增加了Sgk-1的活性、mRNA和蛋白质表达。过氧化氢同样诱导了Sgk-1的表达。抗氧化剂、显性负性Rac以及NADPH氧化酶亚基p22phox的缺失减少了凝血酶诱导的Sgk-1表达。抑制p38丝裂原活化蛋白激酶、磷脂酰肌醇3激酶和磷脂酰肌醇依赖性激酶-1可阻止凝血酶诱导的Sgk-1表达。凝血酶或Sgk-1过表达增强了TF表达和促凝活性，而激酶缺陷型Sgk-1减少了凝血酶引起的TF上调，并且在sgk-1基因缺陷（sgk1(-/-)）小鼠的成纤维细胞中未检测到这种上调。同样，地塞米松处理未能在sgk1(-/-)小鼠的肺组织中诱导TF表达和活性。Sgk-1对TF的转录诱导是通过核因子κB介导的。最后，在与PH相关的重塑肺血管中层检测到Sgk-1和TF蛋白。这些数据表明，凝血酶通过NADPH氧化酶、磷脂酰肌醇3激酶、p38丝裂原活化蛋白激酶和磷脂酰肌醇依赖性激酶-1强力诱导Sgk-1，并且Sgk-1对核因子κB的激活介导了凝血酶引起的TF表达和活性。由于增强的促凝活性可促进肺血管重塑，并且Sgk-1和TF存在于重塑肺血管中层，因此该途径可能在PH的血管重塑中起关键作用。
