In the United States alone, over 5 million people suffer from heart failure and the prevalence is still rising. While treatment has improved outcomes, heart failure morbidity and mortality remain unacceptably high. Thus, developing new approaches for treating heart failure based on appreciation of underlying pathophysiologic mechanisms is an important goal. Cardiac remodeling plays a central role in the pathogenesis of heart failure. In this process, an initial event stimulates diffuse changes throughout the left ventricle (LV) including dilatation, hypertrophy and fibrosis which over time lead to deterioration in cardiac function and progression to heart failure. The local cardiac renin-angiotensin system (RAS) is involved in cardiac remodeling. Angiotensin (Ang) II, the main effector molecule of the RAS, stimulates cardiac hypertrophy and fibrosis. Strategies targeting Ang II inhibit remodeling and improve clinical outcomes. An alternative RAS pathway in which angiotensin converting enzyme 2 (ACE2) generates Ang-(1-7), a peptide with anti-growth and cardioprotective effects, from Ang II has been identified in the heart where it is believed to regulate RAS effects. Results from our laboratory and others suggest that cardiac fibroblasts (CFs) rather than cardiomyocytes are the predominant target for both Ang II stimulatory and Ang-(1-7) inhibitory effects, but this issue remains controversial. The Mas protooncogene encodes a 7 transmembrane G protein-coupled receptor that serves as an Ang-(1-7) receptor. Although Mas is present on CFs, questions remain whether it is required for Ang-(1-7) effects and whether Ang-(1-7) signaling involves or is influenced by Ang II receptors which are also found on these cells. We have shown that Mas heterodimerization with the AT1 receptor affects AT1 expression and function. Our preliminary results indicate that the absence of Ang II receptors leads to increased Mas expression but the functional consequence of Mas/AT1 interactions are uncertain. Moreover, fundamental questions about whether altering Mas expression affects cardiac remodeling, the anti-growth effects of Mas depend on the presence of Ang-(1-7) and if Mas cardioprotective effects are mediated through cardiomyocytes or CFs still need to be addressed. The proposed experiments will determine if: 1. Mas receptor is required for Ang-(1-7) effects in cardiac fibroblasts and whether increasing Mas enhances fibroblast functions related to remodeling, 2. The presence of Ang II receptors modifies Ang-(1-7) effects that require the Mas receptor and the nature of the interaction, and 3. The level of Mas receptor expression and its overexpression in cardiomyocytes compared to cardiac fibroblasts alters Ang-(1-7) effects on post-MI cardiac remodeling. The results of these studies will provide essential information to help determine the role of Mas in cardiac remodeling and to assess its potential as a target for preventing and treating heart failure.
Mas has been identified as a receptor for Ang-(1-7), a peptide which is believed to inhibit maladaptive cardiac remodeling and favorably affect cardiac function. Although the Mas receptor is present on cardiac fibroblasts, its role in mediating Ang-(1-7) effects on cardiac remodeling is not known. This project is designed to determine if Mas is a potential target for therapeutic strategies for preventing and treating heart failure by assessing if Ang-(1-7) effects on cardiac fibroblast functions involved in remodeling require the Mas receptor, whether other angiotensin receptors mediate or influence these Ang-(1-7) effects and whether altering Mas expression in the post-MI heart affects the extent of cardiac remodeling.
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