Angiotensin Receptor AT1 in Cardiovascular Cell Control.

本申请建议继续、扩展和增加新的角度来研究 血管紧张素II（Ang II）在心肌细胞重塑中的作用及其信号机制。 细胞外信号应答中表皮受体和血管紧张素Ⅱ 1型受体之间的相互作用 激酶（ERK），以及几种非受体酪氨酸激酶和酪氨酸磷酸酶的参与 其包括Janus激酶（JAK 2）、富含脯氨酸的酪氨酸激酶（PYK 2）、含SH 2的磷酸酶-2和- 1（SHP-2和SHP-1）蛋白激酶C（特别是PKC-δ）。它们与其他的植物形成一个巨大的复合体， caffold蛋白Gab 1和小G蛋白Rap 1，它们负责激活cJun NH 2- 激酶（JNK），细胞迁移，并使这些细胞响应于他汀类药物的有利作用。 为研究AT 1延长表达的信号转导机制提供了一个新的视角 由AT 2. 基于我们的初步发现，心脏肥大发生在压力超负荷之前，压力超负荷会诱导心肌肥厚。 血管紧张素II 2型受体（AT 2）表达在长期增加之前， 1受体（AT 1）表达，我们将评估压力超负荷诱导心脏 肥大和AT 1的表达由AT 2控制，AT 2激活转录因子早幼粒细胞 锌指蛋白这些研究将为深入了解心血管疾病的发病机制提供重要的线索 重塑，并将有助于开发具体的治疗措施和预防方法， 科普由于心血管重塑而导致的病态和致命疾病。

This application proposes to continue, extend and add new angles to the investigation of the role of angiotensin II (Ang II) in myocyte remodeling and signaling mechanisms for it. It is based on new findings of cross-talk between epidermal receptor and the Ang II type 1 (AT1) receptor in extracellular signal-response kinase (ERK), as well as involvement of several non-receptor tyrosine kinases and tyrosine phosphatases which include Janus kinase (JAK2), proline rich tyrosine kinase (PYK2), SH2 containing phosphatase-2 and - 1 (SHP-2 and SHP-1) protein kinases C (particularly PKC-delta). They form a large complex with other ¿caffold proteins Gab1, and small G-protein Rap1, and they are responsible for activation of cJun NH2- kinase (JNK), cellular migration and make these cells responsive to favorable action of statins. We propose to add a new angle to studies on signaling mechanism regulating prolonged expressionof AT1 byAT2. Based on our preliminary finding that cardiac hypertrophy is preceded by pressure overload, which induces a marked increase in the angiotensin II type 2 receptor (AT2) expression before long term increase in the type 1 receptor (AT1) expression, we will evaluate the hypothesis that pressure overload induced cardiac hypertrophy and AT1 expression is controlled by AT2, which activate the transcription factor promyelocytic zinc finger protein PLZF. These studies will provide important insights into the mechanism of cardiovascular remodeling and will be useful for developing specific therapeutic remedies and preventative approaches to cope with morbid and mortal diseases due to cardiovascular remodeling.