REGULATION OF CARDIAC HYPERTROPHY BY ANGIOTENSINS

肾素血管紧张素系统（RAS）对维持所有哺乳动物的体积稳态至关重要。主要的效应肽，血管紧张素II （Ang II）也被证明影响细胞生长和分化，凋亡和代谢。我们发展了两个主要的研究领域，第一个是心脏内RAS。我们已经证明心脏细胞含有并且能够合成Ang II。最近，我们已经证明RAS成分的基因在心肌细胞和成纤维细胞中受到不同的调节。我们和其他人提供了间接证据，表明局部RAS参与体内心脏肥厚。Ang II参与心脏肥厚是重要的，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）效应。我们已经证明Ang II通过1型质膜受体（AT1）刺激心肌细胞和成纤维细胞的生长，而2型受体（AT2）反对AT1的积极生长作用。我们还发现并表征了核膜上的Ang II结合位点，其他人已经表明细胞内的Ang II激活离子通道，并且Ang II刺激孤立细胞核上的基因转录。我们现在已经将这些体外研究结果扩展到体内模型。使用含有angii编码序列并靶向心脏的表达载体，我们已经显示了小鼠双室心脏肥厚的发展。这是第一个体内数据，表明心肌细胞内Ang II水平升高，导致血压和循环中Ang II水平正常的动物心脏肥大。鉴于观察到心脏内RAS成分表达水平升高与心脏肥厚和心肌梗死相关，需要确定Ang II在心脏内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，并结合分子、细胞和生化方法来确定心脏内Ang II的合成途径，并确定Ang II在心脏肥厚和基因表达方面的作用。

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.