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。血管紧张素II(Ang II)也被证明影响细胞的生长和分化、凋亡和新陈代谢。我们已经发展了两个主要的研究领域，第一个是心内RAS。我们已经证明，心肌细胞含有并能够合成Ang II。最近，我们证明了RAS组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，证明局部RAS参与了体内心肌肥厚。血管紧张素转换酶II在心肌肥大中的作用很重要，因为这一过程是心血管死亡率增加的主要危险因素。第二个领域是Ang II诱导的信号转导和细胞作用，包括Ang II的细胞内效应。我们已经证明，Ang II通过第一型质膜受体(AT1)刺激心肌细胞和成纤维细胞的生长，而第二型受体(AT2)与AT1的正生长效应相反。我们还鉴定并鉴定了核膜上的Ang II结合部位，其他研究表明，细胞内Ang II激活离子通道，Ang II刺激离体核上的基因转录。我们现在已经将这些体外研究结果扩展到体内模型。利用含有Ang II编码序列的针对心脏的表达载体，我们展示了小鼠双室心肌肥厚的发展过程。这是首次有体内数据表明心肌细胞内Ang II水平升高，导致血压正常、循环中Ang II水平正常的动物心肌肥大。鉴于观察到心脏内RAS组分的表达水平与心肌肥厚和心肌梗死相关，需要确定Ang II在基因表达和细胞生长中的作用途径的重要性。我们建议使用体外和体内模型，以及结合分子、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在心肌肥大和基因表达方面的内分泌作用的重要性。

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.