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.
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