Tyrosine Phosphatases and Endothelial Dysfunction

酪氨酸磷酸酶和内皮功能障碍

• 批准号: 6458188
• 负责人: HUA TANG
• 金额: $ 19.2万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6458188
• 关键词: angiotensin II; angiotensin receptor; biological signal transduction; cell adhesion molecules; enzyme activity; free radical oxygen; isozymes; plasminogen activator inhibitors; protein tyrosine phosphatase; renin angiotensin system; tissue /cell culture; vascular endothelium

Studies have indicated that renin-angiotensin system (RAS) and reactive oxygen species (ROS) impact on , endothelial function and are involved in cardiovascular remodeling associated with hypertension, atherosclerosis and heart failure. RAS and ROS promote the expression of plasminogen activator inhibitor-1 (PAI-1), thus interrupting the balance of fibrinolysis. RAS and ROS also stimulate the expression of endothelial-leukocyte adhesion molecules and promote the adhesion of monocytes to monolayers of endothelial cells, which is the earliest detectable event in the pathogenesis of atherosclerosis. However, the molecular mechanisms of angiotensin II (Ang II) and ROS in the regulation of these genes expression are largely unknown. We have demonstrated that enzymatic activity of tyrosine phosphatase SHP-2 plays a negative role in the signal transduction of angiotensin II type-1 receptor (AT1). We also have accumulated substantial preliminary data indicating that tyrosine phosphatases SHP-2 and SHP-1 are the direct targets of ROS and may regulate ROS actions in endothelial cells. The proposed studies will test the hypothesis that tyrosine phosphatases SHP- 2 and SHP-1 play important roles in RAS- and ROS-mediated expression of PAI-1 and cell adhesion molecules in endothelial cells. Using cultured endothelial cells, we will :1) Determine the role of SHP-2 activity in Ang II-induced endothelial dysfunction; 2) Reveal mechanisms by which SHP-2 affects AT1 receptor signal transduction; and 3) Determine roles and mechanisms of SHP-1 and SHP-2 in ROS-mediated signal transduction and gene expression. The present approach, in which molecular, biochemical and cell biological methods are combined, will generate critical information regarding the roles and mechanisms of tyrosine phosphatases SHP-1 and SHP-2 in RAS- and ROS-mediated endothelial dysfunction and will lead to the identification of specific sites of intervention in the treatment of cardiovascular diseases.

研究表明，肾素-血管紧张素系统（RAS）和活性氧（ROS）影响内皮功能，并参与高血压、动脉粥样硬化和心力衰竭相关的心血管重塑。RAS和ROS促进纤溶酶原激活物抑制剂-1（派-1）的表达，从而破坏纤溶平衡。RAS和ROS还刺激内皮细胞-白细胞粘附分子的表达，促进单核细胞与内皮细胞单层的粘附，这是动脉粥样硬化发病机制中最早可检测到的事件。然而，血管紧张素II（Ang II）和活性氧在这些基因的表达调控的分子机制在很大程度上是未知的。我们已经证明，酪氨酸磷酸酶SHP-2的酶活性在血管紧张素II 1型受体（AT 1）的信号转导中起着负作用。我们还积累了大量的初步数据表明，酪氨酸磷酸酶SHP-2和SHP-1是ROS的直接靶点，并可能调节ROS在内皮细胞中的作用。这些研究将验证酪氨酸磷酸酶SHP- 2和SHP-1在RAS和ROS介导的派-1和细胞粘附分子在内皮细胞中的表达中起重要作用的假设。利用培养的内皮细胞，我们将：1）确定SHP-2活性在Ang II诱导的内皮功能障碍中的作用; 2）揭示SHP-2影响AT 1受体信号转导的机制; 3）确定SHP-1和SHP-2在ROS介导的信号转导和基因表达中的作用和机制。目前的方法，其中分子，生物化学和细胞生物学方法相结合，将产生关于酪氨酸磷酸酶SHP-1和SHP-2在RAS和ROS介导的内皮功能障碍的作用和机制的关键信息，并将导致在心血管疾病的治疗干预的特定位点的识别。