REGULATION OF CARDIAC HYPERTROPHY BY ANGIOTENSINS

血管紧张素对心脏肥大的调节

• 批准号: 6389132
• 负责人: KENNETH Melvin BAKER
• 金额: $ 26.69万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-10 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6389132
• 关键词: angiotensin II; angiotensin receptor; autocrine; binding sites; cardiac myocytes; cell growth regulation; fibroblasts; gene expression; genetically modified animals; heart cell; heart dimension /size; hormone biosynthesis; hormone regulation /control mechanism; laboratory mouse; laboratory rat; newborn animals; renin angiotensin system; ventricular hypertrophy

The renin angiotensin system (RAS) is critical for the maintenance of volume homeostasis in all mammalian species. The primary effector peptide, angiotensin II (Ang II) has also been demonstrated to affect cellular growth and differentiation, apoptosis, and metabolism. We have developed two principal areas of investigation, the first being the intracardiac RAS. We have shown that cardiac cells contain and are capable of synthesizing Ang II. More recently, we have demonstrated that the genes for RAS components are differentially regulated in cardiac myocytes and fibroblasts. We and others have provided indirect evidence that local RAS is involved in in vivo cardiac hypertrophy. The involvement of Ang II in cardiac hypertrophy is important, as this process is a major risk factor associated with increased cardiovascular mortality. The second area is Ang II-induced signal transduction and cellular actions, including the intracellular (intracrine) effects of Ang II. We have shown that Ang II, acting via the type one, plasma membrane receptor (AT1) stimulates the growth of cardiac myocytes and fibroblasts, and that the type two receptor (AT2) opposes the positive growth effects of AT1. We have also identified and characterized an Ang II binding site on the nuclear envelope, and others have shown that intracellular Ang II activates ion channels, and that Ang II stimulates gene transcription on isolated nuclei. We have now extended these in vitro findings, to an in vivo model. Using an expression vector which contains the coding sequence for Ang II and is targeted to the heart, we have shown the development of biventricular cardiac hypertrophy in the mouse. These are the first in vivo data demonstrating that increased intracellular levels of Ang II in cardiac myocytes, result in cardiac hypertrophy in animals with normal blood pressure and circulating levels of Ang II. In light of the observation that the expression levels for the intracardiac RAS components are increased in association with cardiac hypertrophy and myocardial infarction, the importance of an intracrine route of action for Ang II on gene expression and cellular growth needs to be determined. We propose using in vitro and in vivo models, and a combination of molecular, cellular, and biochemical approaches to define the synthesis pathways for intracardiac Ang II, and establish the importance of an intracrine action for Ang II, with respect to cardiac hypertrophy and gene expression.

肾素血管紧张素系统（RAS）对于维持所有哺乳动物物种的体积稳态至关重要。主要的效应肽，血管紧张素II（ANG II）也已被证明会影响细胞生长和分化，凋亡和代谢。我们已经开发了两个主要调查领域，第一个是心脏内RAS。我们已经表明心脏细胞包含并能够合成ANG II。最近，我们证明了RAS成分的基因在心肌细胞和成纤维细胞中受到差异调节。我们和其他人提供了间接证据，表明局部RA参与体内心脏肥大。 ANG II参与心脏肥大很重要，因为此过程是与心血管死亡率升高有关的主要危险因素。第二个区域是ANG II诱导的信号转导和细胞作用，包括Ang II的细胞内（内分环）作用。我们已经表明，ANG II通过第一型作用，质膜受体（AT1）刺激心肌细胞和成纤维细胞的生长，而第二型受体（AT2）则反对AT1的正生长效应。我们还鉴定并表征了核包膜上的ANG II结合位点，而其他人则表明细胞内ANG II激活了离子通道，并且ANG II刺激了分离的核上的基因转录。现在，我们已经将这些体外发现扩展到了体内模型。使用包含ANG II的编码序列并针对心脏的表达矢量，我们显示了小鼠中双心心心肥大的发展。这些是第一个体内数据，表明心肌细胞中ANG II的细胞内水平升高，导致血压正常和ANG循环水平的动物的心脏肥大。鉴于观察到，心脏内RAS成分的表达水平与心脏肥大和心肌梗塞相关，因此需要确定ANG II对基因表达和细胞生长的内部作用途径的重要性。我们建议使用体外和体内模型，以及分子，细胞和生化方法的组合来定义心脏内ANG II的合成途径，并确定与心脏肥大和基因表达相对于ANG II的基本作用的重要性。