REGULATION OF CARDIAC HYPERTROPHY BY ANGIOTENSINS

血管紧张素对心脏肥大的调节

• 批准号: 2735169
• 负责人: KENNETH Melvin BAKER
• 金额: $ 22.61万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-03 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2735169
• 关键词: angiotensin II; biological signal transduction; cellular pathology; disease /disorder model; heart enlargement; heart pharmacology; hormone receptor; immunocytochemistry; inhibitor /antagonist; laboratory rat; mechanical pressure; neutralizing antibody; polymerase chain reaction; radioimmunoassay; receptor binding; renin angiotensin system; stretch reflex; tissue /cell culture; transfection

The renin angiotensin system has a major role in the regulation of cardiovascular, renal and endocrine functions. Angiotensin II can activate intracellular responses including calcium mobilization, stimulation of sodium/hydrogen exchange, inositol phosphate metabolism, diacylglycerol production, protein kinase C, Raf-1 kinase hyperphosphorylation, the mitogen-activated protein kinase cascade, phosphorylation of nuclear lamina and transcriptional regulation of immediate and intermediate response genes. Recent published data support the concept that this peptide plays an important role in the compensatory left ventricular hypertrophy that occurs in association with pressure overload and in ventricular remodeling following myocardial infarction. Our data, obtained in both in vitro and in vivo experimental models, suggest that there is an intracardiac renin angiotensin system, which may contribute to these responses. Recent in vitro data indicate that stimulation of various signal transduction pathways and growth, in response to static stretch, may be mediated by local production and release of angiotensin II. We will test the hypotheses that the intracardiac renin angiotensin system is regulated by mechanical stretch and humoral stimuli and that activation of the intracardiac renin angiotensin system is a prerequisite for the development of cardiac hypertrophy in vivo. Regulation will be defined in an in vitro cell culture model using mechanical and humoral stimuli and in vivo using experimental models of pressure overload and myocardial infarction. Regulated components of the renin angiotensin system will be determined using pharmacological inhibitors; neutralizing antibodies; radioimmunoassay; radiolabeled receptor binding; quantitative, multiplex, reverse transcriptase polymerase chain reaction; in situ hybridization; and immunohistochemical analyses. The contribution of individual renin angiotensin system components will be determined utilizing gene transfer technology. Determining the importance of, and mechanisms by which an intracardiac renin angiotensin system is regulated has significant implications for understanding the biological role of this system in association with developmental, physiological and pathological processes. These directions have the broader application of contributing to the successful management of cardiovascular disease.

肾素血管紧张素系统在调节 心血管、肾脏和内分泌功能。 血管紧张素II可以 激活细胞内反应包括钙动员， 刺激钠/氢交换，磷酸肌醇代谢， 甘油二酯生成，蛋白激酶C，Raf-1激酶 过度磷酸化，丝裂原活化蛋白激酶级联， 核纤层的磷酸化和转录调控 立即和中间反应基因。 最近公布的数据支持 这种肽在代偿性脑损伤中起重要作用的概念， 与压力相关的左心室肥大 超负荷和心肌梗死后心室重构。 我们在体外和体内实验模型中获得的数据， 提示心内存在一种肾素血管紧张素系统， 有助于这些反应。 最近的体外数据表明， 刺激各种信号转导途径和生长， 对静态拉伸的反应，可能是由局部产生介导的， 释放血管紧张素II。 我们将测试的假设， 心内肾素血管紧张素系统受机械牵张调节 和体液刺激以及心内肾素的激活 血管紧张素系统是心脏发育的先决条件， 体内肥大。 将在体外细胞中定义调节 使用机械和体液刺激的培养模型和体内使用 压力超负荷和心肌梗死的实验模型。 将确定肾素血管紧张素系统的调节组分 使用药理学抑制剂;中和抗体; 放射免疫测定;放射性标记受体结合;定量，多重， 逆转录聚合酶链反应;原位杂交; 和免疫组织化学分析。 单个肾素的贡献 血管紧张素系统成分将利用基因转移 技术. 确定一项战略的重要性及其机制， 心内肾素血管紧张素系统的调节具有重要意义 对理解该系统的生物学作用的影响， 与发育、生理和病理过程的联系。 这些方向具有更广泛的应用，有助于 心血管疾病的成功管理。