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

Mas 受体是血管紧张素 (1-7) 在心脏重塑中的作用所必需的

• 批准号: 8293171
• 负责人: Barry H Greenberg
• 金额: $ 34.98万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8293171
• 关键词: AGTR2 gene; Address; Affect; Amino Acids; Angiotensin II; Angiotensin II Receptor; Angiotensin Receptor; Animal Model; Cardiac; Cardiac Myocytes; Cells; Cleaved cell; Clinical; Deterioration; Developed Countries; Development; Diffuse; Dilatation - action; Disease Progression; Event; Fibroblasts; Fibrosis; G-Protein-Coupled Receptors; Goals; Growth; Health; Heart; Heart Hypertrophy; Heart failure; Heterodimerization; Homologous Gene; Human; Hypertrophy; Laboratories; Lead; Left ventricular structure; Mediating; Morbidity - disease rate; Myocardial Infarction; Myocardium; Nature; Outcome; Pathogenesis; Pathway interactions; Patients; Peptides; Peptidyl-Dipeptidase A; Play; Population; Prevalence; Process; Property; Proto-Oncogenes; Relative (related person); Renin-Angiotensin System; Role; Signal Transduction; Testing; Time; United States; angiotensin I (1-7); autocrine; base; design; improved; in vivo; injured; mortality; novel strategies; novel therapeutic intervention; overexpression; pandemic disease; paracrine; prevent; receptor; receptor expression; research study; therapeutic target; treatment strategy

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.

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。虽然治疗改善了结果，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，在了解潜在的病理生理机制的基础上开发治疗心力衰竭的新方法是一个重要的目标。心脏重构在心力衰竭的发病机制中起着核心作用。在这一过程中，初始事件刺激整个左心室（LV）的弥漫性变化，包括扩张、肥厚和纤维化，随着时间的推移导致心功能恶化并进展为心力衰竭。局部心脏肾素-血管紧张素系统（RAS）参与心脏重构。血管紧张素（Ang） II是RAS的主要效应分子，刺激心肌肥大和纤维化。针对Ang II的策略抑制重塑并改善临床结果。在另一种RAS途径中，血管紧张素转换酶2 （ACE2）在心脏中从Ang II生成Ang-(1-7)，一种具有抗生长和心脏保护作用的肽，据信它可以调节RAS的作用。我们实验室和其他人的结果表明，心脏成纤维细胞（CFs）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，但这一问题仍然存在争议。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CFs中，但对于Ang-(1-7)效应是否需要Mas，以及Ang-(1-7)信号是否涉及或受这些细胞上发现的Ang II受体的影响，仍然存在疑问。我们已经证明，Mas与AT1受体的异二聚化影响AT1的表达和功能。我们的初步结果表明，缺乏Ang II受体导致Mas表达增加，但Mas/AT1相互作用的功能后果尚不确定。此外，关于Mas表达的改变是否会影响心脏重塑、Mas的抗生长作用取决于Ang-(1-7)的存在以及Mas的心脏保护作用是通过心肌细胞还是CFs介导的等基本问题仍然需要解决。提出的实验将决定：1。Mas受体是心脏成纤维细胞中Ang-(1-7)作用所必需的，以及Mas增加是否会增强成纤维细胞与重塑相关的功能，2。2 . Ang II受体的存在改变了需要Mas受体的Ang-(1-7)效应和相互作用的性质；与心肌成纤维细胞相比，心肌细胞中Mas受体的表达水平及其过表达改变了Ang-(1-7)对心肌梗死后心脏重构的影响。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目标的潜力。公共卫生相关性：Mas已被确定为Ang-(1-7)的受体，Ang-(1-7)是一种肽，被认为可以抑制不适应的心脏重塑并有利地影响心功能。虽然Mas受体存在于心脏成纤维细胞中，但其在介导Ang-(1-7)对心脏重塑的作用尚不清楚。该项目旨在通过评估Ang-(1-7)对参与重构的心脏成纤维细胞功能的影响是否需要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，以及改变心肌梗死后心脏中Mas表达是否影响心脏重构的程度，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。

项目成果

Identification of intracellular proteins and signaling pathways in human endothelial cells regulated by angiotensin-(1-7).

• DOI: 10.1016/j.jprot.2015.09.020
• 发表时间: 2016-01-01
• 期刊: Journal of proteomics
• 影响因子: 3.3
• 作者: Meinert C;Gembardt F;Böhme I;Tetzner A;Wieland T;Greenberg B;Walther T
• 通讯作者: Walther T

An ACE for my sweet heart.

给我亲爱的心的 ACE。

• DOI: 10.1016/j.jacc.2011.11.021
• 发表时间: 2012
• 期刊: Journal of the American College of Cardiology
• 影响因子: 24
• 作者: Greenberg,Barry;Cowling,RandyT
• 通讯作者: Cowling,RandyT

Further intracellular proteins and signaling pathways regulated by angiotensin-(1–7) in human endothelial cells

人内皮细胞中血管紧张素-(1â7) 调节的其他细胞内蛋白和信号通路

• DOI: 10.1016/j.dib.2016.12.004
• 发表时间: 2017
• 期刊: Data in Brief
• 影响因子: 1.2
• 作者: Meinert C;Kohse F;Boehme I;Gembardt F;Tetzner A;Wieland T;Greenberg B;Walther T
• 通讯作者: Walther T

Targeting the ACE2-Ang-(1-7) pathway in cardiac fibroblasts to treat cardiac remodeling and heart failure.

• DOI: 10.1016/j.yjmcc.2010.12.003
• 发表时间: 2011-10
• 期刊: Journal of molecular and cellular cardiology
• 影响因子: 5
• 作者: Iwata M;Cowling RT;Yeo SJ;Greenberg B
• 通讯作者: Greenberg B

Effects of ACE2 inhibition in the post-myocardial infarction heart.

• DOI: 10.1016/j.cardfail.2010.04.002
• 发表时间: 2010-09
• 期刊: JOURNAL OF CARDIAC FAILURE
• 影响因子: 6
• 作者: Kim, Myung-A;Yang, Dongheon;Kida, Keisuke;Molotkova, Natalia;Yeo, Seon Ju;Varki, Nissi;Iwata, Michikado;Dalton, Nancy D.;Peterson, Kirk L.;Siems, Wolf-Eberhard;Walther, Thomas;Cowling, Randy T.;Kjekshus, John;Greenberg, Barry
• 通讯作者: Greenberg, Barry