The Mas Receptor is Required for Angiotensin-(1-7) Effects in Cardiac Remodeling

描述（由申请人提供）：仅在美国，就有超过500万人患有心力衰竭，并且患病率仍在上升。虽然治疗改善了结局，但心力衰竭的发病率和死亡率仍然高得令人无法接受。因此，基于对潜在病理生理机制的认识开发治疗心力衰竭的新方法是一个重要目标。心脏重构在心力衰竭的发病机制中起着核心作用。在此过程中，初始事件刺激整个左心室（LV）的弥漫性变化，包括扩张、肥大和纤维化，随着时间的推移，这些变化导致心脏功能恶化并进展为心力衰竭。心脏局部的肾素-血管紧张素系统（RAS）参与心脏重塑。血管紧张素II（Angiotensin II，Ang II）是RAS的主要效应分子，可刺激心肌肥厚和纤维化。靶向Ang II的策略抑制重塑并改善临床结果。已经在心脏中鉴定了血管紧张素转化酶2（ACE 2）从Ang II产生Ang-（1-7）（一种具有抗生长和心脏保护作用的肽）的替代RAS途径，其中认为其调节RAS作用。我们实验室和其他实验室的结果表明，心脏成纤维细胞（CF）而不是心肌细胞是Ang II刺激和Ang-（1-7）抑制作用的主要靶点，但这一问题仍存在争议。Mas原癌基因编码一个7跨膜G蛋白偶联受体，作为Ang-（1-7）受体。尽管Mas存在于CF上，但问题仍然存在，它是否是Ang-（1-7）作用所必需的，以及Ang-（1-7）信号传导是否涉及也在这些细胞上发现的Ang II受体或受其影响。我们已经表明，Mas与AT 1受体的异源二聚化影响AT 1的表达和功能。我们的初步结果表明，血管紧张素II受体的情况下，导致Mas的表达增加，但Mas/AT 1相互作用的功能后果是不确定的。此外，关于Mas表达的改变是否影响心脏重塑、Mas的抗生长作用是否依赖于Ang-（1-7）的存在以及Mas的心脏保护作用是否通过心肌细胞或CFs介导的基本问题仍需要解决。建议的实验将确定是否：1。Mas受体是心脏成纤维细胞中Ang-（1-7）作用所必需的，以及增加Mas是否增强与重塑相关的成纤维细胞功能。Ang II受体的存在改变了Ang-（1-7）的作用，其需要Mas受体和相互作用的性质，以及3. Mas受体表达水平及其在心肌细胞中的过表达与心肌成纤维细胞相比改变了Ang-（1-7）对MI后心脏重塑的作用。这些研究的结果将提供必要的信息，以帮助确定Mas在心脏重塑中的作用，并评估其作为预防和治疗心力衰竭的靶点的潜力。公共卫生相关性：Mas已被鉴定为Ang-（1-7）的受体，Ang-（1-7）是一种被认为抑制适应不良的心脏重塑并有利地影响心脏功能的肽。尽管Mas受体存在于心脏成纤维细胞上，但其在介导Ang-（1-7）对心脏重塑的作用中的作用尚不清楚。该项目旨在通过评估Ang-（1-7）对参与重塑的心脏成纤维细胞功能的作用是否需要Mas受体，其他血管紧张素受体是否介导或影响这些Ang-（1 -7）作用以及改变MI后心脏中Mas表达是否影响心脏重塑的程度来确定Mas是否是预防和治疗心力衰竭的治疗策略的潜在靶点。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.