Angiotensin Receptor AT1 in Vascular Cell Control.

血管紧张素受体 AT1 在血管细胞控制中的作用。

• 批准号: 6638477
• 负责人: TADASHI INAGAMI
• 金额: $ 33.98万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-10 至 2006-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6638477
• 关键词: angiogenesis; angiotensin II; angiotensin receptor; biological signal transduction; cell growth regulation; enzyme activity; enzyme induction /repression; free radical oxygen; growth factor receptors; immunologic assay /test; laboratory rat; metalloendopeptidases; mitogen activated protein kinase; protein structure function; protein tyrosine kinase; protein tyrosine phosphatase; receptor expression; tissue /cell culture; vascular smooth muscle

DESCRIPTION (Verbatim from the application): The peptide hormone angiotensin II (AngII) contributes to various cardiovascular diseases such as hypertension, atherosclerosis, and heart failure. The growth promoting activity of the AngII type-1 (AT1) receptor is implicated in the progression of cardiovascular remodeling. In vascular smooth muscle cells (VSMC), AngII is believed to transmit its growth-promoting signal through activation of tyrosine kinases (PYK2, Src, JAK, and EGF receptor). We have reported that the transactivation of the EGF receptor (EGFR) by Angli is essential for the activation of ERK and p70 S6 kinase, and subsequent c-Fos induction and protein synthesis by AngII in cultured VSMC. Thus, the EGFR transactivation could play a central role in AngII mediated vascular remodeling. Several mechanisms implicating an upstream tyrosine kinase, reactive oxygen species (ROS) and a metalloprotease-dependent generation of an EGFR ligand are proposed for the transactivation. However, a huge void remains in our knowledge in terms of the mechanism by which AngII/AT1 activates the EGFR. Also, it is not clear whether other signals such as activation of p38 and JNK MAP kinases by AngII are under control of transactivation, if they are regulated by other tyrosine kinases, or if a tyrosine phosphatase such as SHP-2 is involved. Thus, we will evaluate the hypothesis that the tyrosine kinases (PYK2 and JAK2). the tyrosine phosphatase SHP-2. ROS. and the metalloprotease ADAM regulate activation of EGFR and/or MAP kinases by AngII in VSMC. The specific aims of this application are 1) to investigate the roles of the following factors in the EGFR transactivation mechanisms by AngII (PYK2, JAK2, ROS, metalloprotease); 2) to investigate the involvement of the tyrosine kinases in activation of p38 and JNK by AnglI; 3) to investigate the role of SHP-2 in regulation of PYK2; 4) to investigate the role of SHP-2 in regulation of MAP kinases by AngII. These studies will unravel the initial key mechanism by which vasculotrophic factors such as Angil regulate vascular remodeling. Moreover, the clarification of the indispensable hypertrophic and hyperplastic signals in combination with the identification of key enzymes (kinases and/or phosphatases) will provide potential therapeutic targets in cardiovascular diseases.

描述（申请逐字记录）：肽激素血管紧张素 II (AngII) 会导致各种心血管疾病，例如高血压、 动脉粥样硬化和心力衰竭。 AngII的生长促进活性 1 型 (AT1) 受体与心血管疾病的进展有关 重塑。在血管平滑肌细胞 (VSMC) 中，AngII 被认为 通过激活酪氨酸激酶传递促生长信号 （PYK2、Src、JAK 和 EGF 受体）。我们报道了反式激活 Angli 的 EGF 受体 (EGFR) 对 ERK 的激活至关重要 p70 S6 激酶，以及随后的 c-Fos 诱导和 AngII 的蛋白质合成 培养的VSMC。因此，EGFR 反式激活可能在 AngII 介导的血管重塑。涉及上游的几种机制 酪氨酸激酶、活性氧 (ROS) 和金属蛋白酶依赖性 建议生成 EGFR 配体用于反式激活。然而，一个 关于 AngII/AT1 的作用机制，我们的知识仍然存在巨大空白 激活 EGFR。此外，尚不清楚是否存在其他信号，例如 AngII 对 p38 和 JNK MAP 激酶的激活受到以下因素的控制 反式激活，如果它们受到其他酪氨酸激酶的调节，或者如果 涉及酪氨酸磷酸酶，例如SHP-2。因此，我们将评估 假设酪氨酸激酶（PYK2 和 JAK2）。酪氨酸磷酸酶 SHP-2。活性氧。金属蛋白酶 ADAM 调节 EGFR 和/或 MAP 的激活 VSMC 中 AngII 激酶。该应用程序的具体目标是 1) 研究以下因素在 EGFR 反式激活中的作用 AngII 机制（PYK2、JAK2、ROS、金属蛋白酶）； 2）调查 酪氨酸激酶参与 AnglI 激活 p38 和 JNK； 3） 研究SHP-2在PYK2调节中的作用； 4）调查 SHP-2 在 AngII 调节 MAP 激酶中的作用。这些研究将揭开 Angil 等血管营养因子的最初关键机制 调节血管重塑。此外，澄清必不可少的 肥厚和增生信号与识别相结合 关键酶（激酶和/或磷酸酶）将提供潜在的治疗作用 心血管疾病的目标。