REGULATION OF CARDIAC HYPERTROPHY BY ANGIOTENSINS

肾素血管紧张素系统（RAS）是维持所有哺乳动物体内容量平衡的关键。主要效应肽血管紧张素II（Ang II）也已被证明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的研究领域，第一个是心内RAS。我们已经证明，心脏细胞含有并能够合成血管紧张素II。最近，我们已经证明，RAS组件的基因差异调节心肌细胞和成纤维细胞。我们和其他人提供了间接证据表明局部RAS参与体内心脏肥大。血管紧张素II参与心脏肥大是重要的，因为这一过程是一个主要的危险因素与心血管死亡率增加。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（内分泌）作用。我们已经表明，血管紧张素II，通过第一型，质膜受体（AT 1）刺激心肌细胞和成纤维细胞的生长，和第二型受体（AT 2）反对AT 1的积极的生长效果。我们还确定和表征了核膜上的血管紧张素II结合位点，并且其他人已经表明细胞内血管紧张素II激活离子通道，并且血管紧张素II刺激分离的细胞核上的基因转录。我们现在已经将这些体外发现扩展到体内模型。使用含有Ang II编码序列并靶向心脏的表达载体，我们已经显示了小鼠双心室心肌肥大的发展。这些是第一个体内数据，证明心肌细胞中Ang II的细胞内水平增加，导致具有正常血压和Ang II循环水平的动物的心脏肥大。鉴于心内RAS组分的表达水平增加与心脏肥大和心肌梗死相关，需要确定Ang II作用于基因表达和细胞生长的内分泌途径的重要性。我们建议使用在体外和体内模型，并结合分子，细胞和生化方法来定义心内血管紧张素II的合成途径，并建立一个intracrine行动的重要性，血管紧张素II，相对于心脏肥大和基因表达。

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.