Hepatocyte growth factor regulates E box-dependent plasminogen activator inhibitor type 1 gene expression in HepG2 liver cells
Hepatocyte growth factor regulates E box-dependent plasminogen activator inhibitor type 1 gene expression in HepG2 liver cells
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DOI：
10.1161/01.atv.0000240318.61359.e3
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发表时间：
2006-10-01
影响因子：
8.7
通讯作者：
Sobel, Burton E.
中科院分区：
文献类型：
--
作者：
Imagawa, Shogo;Fujii, Satoshi;Sobel, Burton E.
目的-我们试图确定多效生长因子，肝细胞生长因子（HGF）的病因机制，作为纤溶酶原激活物抑制剂(PAI)-1肝脏合成的调节因子，PAI -1是纤维蛋白溶解的生理抑制剂和动脉粥样硬化血栓形成的潜在诱导剂。方法与结果- HGF增加人肝源性HepG2细胞条件培养基中PAI-1 mRNA的表达和PAI-1蛋白的积累，并增加小鼠体内肝脏PAI-1 mRNA的表达。HGF诱导的PAI-1 mRNA被丝裂原活化蛋白激酶（MAPK）激酶特异性抑制剂U0126和酪氨酸激酶抑制剂染料木素减弱。HGF增加了人类PAI-1启动子（-829至-36 bp）的活性，缺失和突变分析发现，在-158至-153 bp的位置有一个功能性E盒（5'-CACATG-3'）。电泳迁移率转移分析表明，该E盒结合上游刺激因子（usf）。HGF通过MAPK和酪氨酸激酶途径磷酸化USFs。共转染USF1表达载体可提高PAI-1启动子活性。甾醇调节元件结合蛋白-1减弱HGF诱导的PAI-1启动子活性。结论：由于usf参与碳水化合物和脂质代谢的调节，HGF介导的PAI-1的产生可能在动脉粥样硬化血栓形成和代谢紊乱之间提供了新的联系。靶向HGF信号通路可调节高危患者血栓形成风险。
Objective - We sought to determine the etiologic mechanism of pleiotropic growth factor, hepatocyte growth factor (HGF), as a regulator of hepatic synthesis of plasminogen activator inhibitor (PAI)-1, the physiological inhibitor of fibrinolysis and a potential inducer of atherothrombosis.Methods and Results - HGF increased PAI-1 mRNA expression and PAI-1 protein accumulation in the conditioned media of human liver-derived HepG2 cells, and increased hepatic PAI-1 mRNA expression in vivo in mice. HGF- inducible PAI-1 mRNA was attenuated by U0126, a specific inhibitor of mitogen-activated protein kinase (MAPK) kinase, and genistein, an inhibitor of tyrosine kinase. HGF increased the human PAI-1 promoter (-829 to -36 bp) activity, and deletion and mutation analysis uncovered a functional E box (5'-CACATG-3') at positions -158 to -153 bp. Electrophoretic mobility shift assays demonstrated that this E box binds upstream stimulatory factors (USFs). HGF phosphorylated USFs through MAPK and tyrosine kinase pathways. Co-transfection of USF1 expression vector increased PAI-1 promoter activity. Sterol regulatory element-binding protein-1 attenuated HGF- inducible PAI-1 promoter activity.Conclusions - Because USFs are involved in the regulation of carbohydrates and lipid metabolism, HGF- mediated PAI-1 production may provide a novel link between atherothrombosis and metabolic derangements. Targeting HGF signaling pathway may modulate the thrombotic risk in high-risk patients.