The Renin-Angiotensin II System in Cardiovascular Remodeling

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DESCRIPTION (provided by applicant): The major goal of our studies is to identify the molecular mechanisms underlying the role of Ang II in the development and progression of cardiac fibrosis in the spontaneously hypertensive rat (SHR). An additional goal is to determine the mechanisms underlying the ability of early, short-term application of angiotensin-converting enzyme inhibitors (ACEI) to prevent the development and progression of fibrosis. We have previously found that early, short-term CAP treatment of SHR prevents cardiac fibrosis and may do this by inhibiting the initiation of a pro-fibrotic environment prior to an increase in BP in SHR. This proposal has 3 specific aims: (1) To determine whether early, short-term treatment of SHR with CAP prevents LV remodeling through prolonged blockade of cardiac RAS and whether or not this effect is independent of blood pressure effects. Cardiac function will be monitored by echocardiography, ex vivo perfusion, and hemodynamic studies. Collagen content, distribution, phenotype, and cross-linking will be determined by a combination of biochemical, morphometric, molecular, biological, and Western blot analyses. Ang II and TGF-beta and its receptors will be monitored by biochemical and molecular biological methods. (2) To determine the cellular and molecular mechanisms underlying Ang II-induced cardiac fibrosis in SHR and how they are inhibited by early, short-term CAP. Expression of collagen isoforms and proteins that regulate collagen synthesis (Ang II receptors, TGF-beta) and proteins that regulate collagen degradation (TIMPs, PAl-l) will be determined by RNase protection assays, and Northern and Western blot analyses. (3) To identify the cellular signal transduction cascades in cardiac fibroblasts that mediate the development of cardiac fibrosis by RAS in hypertension. Signaling intermediates will be determined by Western blot analyses. This proposal will utilize SHR, a well-characterized model of genetic hypertension, and it is the first to study Ang II-dependent mechanisms of collagen synthesis and degradation in vivo and in vitro in cardiac fibroblasts, how they change over time, and how they correlate to cardiac function in SHR. These studies will allow us to identify new targets for pharmacological intervention to prevent adverse cardiovascular remodeling in hypertension.