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。主要效应肽血管紧张素 II (Ang II) 也被证明可以影响细胞生长和分化、细胞凋亡和代谢。我们开发了两个主要研究领域，第一个是心内 RAS。我们已经证明心肌细胞含有并能够合成血管紧张素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性调节。我们和其他人提供了局部 RAS 参与体内心脏肥大的间接证据。 Ang II 参与心脏肥大非常重要，因为这一过程是与心血管死亡率增加相关的主要危险因素。第二个领域是 Ang II 诱导的信号转导和细胞作用，包括 Ang II 的细胞内（胞内）作用。我们已经证明，Ang II 通过一型质膜受体 (AT1) 发挥作用，刺激心肌细胞和成纤维细胞的生长，而二型受体 (AT2) 则对抗 AT1 的积极生长作用。我们还鉴定并表征了核膜上的 Ang II 结合位点，其他人也表明细胞内 Ang II 激活离子通道，并且 Ang II 刺激分离细胞核上的基因转录。我们现在已将这些体外研究结果扩展到体内模型。使用包含 Ang II 编码序列并靶向心脏的表达载体，我们显示了小鼠双心室心脏肥大的发展。这些是第一个体内数据，证明心肌细胞内 Ang II 水平升高会导致血压和 Ang II 循环水平正常的动物心脏肥大。鉴于心内 RAS 成分的表达水平增加与心脏肥大和心肌梗塞相关，因此需要确定 Ang II 的内分泌作用途径对基因表达和细胞生长的重要性。我们建议使用体外和体内模型，结合分子、细胞和生化方法来定义心内 Ang II 的合成途径，并确定 Ang II 内分泌作用对于心脏肥大和基因的重要性。表达。