Regulation of Gq Signaling in Cardiac Fibroblasts and its Role in Cardiac Remodel

心脏成纤维细胞 Gq 信号传导的调节及其在心脏重塑中的作用

• 批准号: 9064836
• 负责人: Ulrike Mende
• 金额: $ 48.82万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9064836
• 关键词: Action Potentials; Address; Adult; Affect; Angiotensin II; Arrhythmia; Attention; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Proliferation; Cells; Cessation of life; Characteristics; Chemicals; Collagen; Coronary Arteriosclerosis; Coupled; Cyclic AMP; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotides; Data; Deposition; Development; Disease; Echocardiography; Electrophysiology (science); Engineering; Event; Experimental Models; Extracellular Matrix; Fibroblasts; Fibrosis; GTP-Binding Protein Regulators; Gene Transfer; Generations; Goals; Growth; Guanylate Cyclase; Health; Heart; Heart Hypertrophy; Heart Rate; Heart failure; Histology; Hypertension; Hypertrophy; Infusion procedures; Injury; Knockout Mice; Lead; LoxP-flanked allele; Maps; Measurement; Mechanics; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Myocardium; Myofibroblast; Optics; Organ; Outcome Study; Pathway interactions; Pattern; Phenotype; Phosphorylation; Physiological; Play; Prevention; Proliferating; Property; Protein Isoforms; Pump; RGS Proteins; RGS2 gene; Rattus; Regulation; Reporting; Research; Role; Secondary to; Shapes; Signal Pathway; Signal Transduction; Stress; Techniques; Testing; Tissues; Ventricular; cell type; design; hemodynamics; in vivo; innovation; insight; interdisciplinary approach; interstitial; knock-down; loss of function; novel; periostin; pressure; prevent; programs; promoter; protein expression; receptor; response; scaffold; sildenafil; sudden cardiac death; therapeutic target

DESCRIPTION (provided by applicant): Cardiac fibroblasts (CF) and cardiac myocytes (CM) play central roles in the cardiac remodeling response that occurs in many cardiovascular diseases. It entails CM hypertrophy, CF activation and increased extracellular matrix deposition, and often leads to heart failure and arrhythmias. CF increasingly attract attention as therapeutic targets but they have received much less attention than CM so far. The Gq signaling pathway is well known to play a central role in cardiac remodeling and to lead to pro-fibrotic effects in CF. However, there is a fundamental gap in understanding of the mechanisms that regulate Gq signaling in CF and how Gq signaling in CF crossregulates CM and affects the cardiac remodeling response to hemodynamic stress. We recently showed that the negative Gq regulator RGS2 (Regulator of G protein Signaling 2) is expressed in CF and uniquely susceptible to regulation compared to other RGS isoforms. We also show that RGS2 is up- regulated by cAMP, which is at the center of the Gs signaling pathway with well known anti-fibrotic effects. In addition, cGMP is known to phosphorylate RGS2 and also exert anti-fibrotic effects. However, the underlying mechanisms of action and potential crosstalk with the Gq signaling pathway in CF are not yet well understood. The long-term goal of this research program is to advance understanding of the regulation of Gq signaling in CF and its role in determining the cardiac remodeling response to stress. Using multi-scale experimental approaches will test our central hypothesis that Gq-mediated signaling in CF and its regulation by cyclic nucleotides not only determines CF responses but crossregulates CM function and thereby influences cardiac remodeling. The Specific Aims are: (1) To determine the role of RGS2 as a mediator of anti-fibrotic cAMP effects in adult rat ventricular CF and the mechanisms of this novel crosstalk between the Gs and Gq signaling pathways; (2) To determine the effect of altered Gq signaling in CF on CM and the integrated functional response of cardiac microtissues; and (3) To determine the effect of fibroblast-restricted RGS2 deletion on Gq- mediated cardiac remodeling in vivo. We will use cardiac microtissues and intact mice, in which Gq signaling can be selectively altered in CF, as novel experimental models. Using multidisciplinary approaches, we will characterize structural (fibrosis and hypertrophy) and electrical remodeling responses, assess functional consequences on contractile function and heart rate regulation, and determine underlying mechanisms. Further innovation lies in addressing the role of CF-to-CM cross-regulation on the integrated remodeling response. The proposed study is significant, because the new insights we will gain about Gq-mediated signaling in CF, its regulation and the resulting consequences for CF, CM and their integrated remodeling response are expected to aid in the development of new strategies targeting cardiac remodeling for heart failure treatment/prevention.

描述（由申请人提供）：心脏成纤维细胞（CF）和心肌细胞（CM）在许多心血管疾病中发生的心脏重塑反应中发挥核心作用。它导致 CM 肥大、CF 激活和细胞外基质沉积增加，并常常导致心力衰竭和心律失常。 CF 作为治疗靶点越来越受到关注，但迄今为止，它们受到的关注远低于 CM。众所周知，Gq 信号通路在心脏重塑中发挥核心作用，并导致 CF 的促纤维化作用。然而，对于调节 CF 中 Gq 信号传导的机制以及 CF 中 Gq 信号传导如何交叉调节 CM 并影响心脏重塑对血流动力学应激的反应的理解存在根本差距。我们最近表明，负 Gq 调节因子 RGS2（G 蛋白信号传导调节因子 2）在 CF 中表达，与其他 RGS 亚型相比，它独特地容易受到调节。我们还发现 RGS2 被 cAMP 上调，cAMP 是 Gs 信号通路的核心，具有众所周知的抗纤维化作用。此外，已知 cGMP 可使 RGS2 磷酸化并发挥抗纤维化作用。然而，CF 中的潜在作用机制以及与 Gq 信号通路的潜在串扰尚不清楚。该研究项目的长期目标是加深对 CF 中 Gq 信号传导调节及其在确定心脏重构对应激反应中的作用的了解。使用多尺度实验方法将检验我们的中心假设，即 CF 中 Gq 介导的信号传导及其通过环核苷酸的调节不仅决定 CF 反应，而且交叉调节 CM 功能，从而影响心脏重塑。具体目标是： (1) 确定 RGS2 在成年大鼠心室 CF 中作为抗纤维化 cAMP 作用的介质的作用，以及 Gs 和 Gq 信号通路之间这种新型串扰的机制； (2) 确定CF中Gq信号改变对CM和心脏微组织综合功能反应的影响； (3)确定成纤维细胞限制性RGS2缺失对Gq介导的体内心脏重塑的影响。我们将使用心脏微组织和完整小鼠作为新的实验模型，其中 Gq 信号传导可以在 CF 中选择性改变。使用多学科方法，我们将表征结构（纤维化和肥大）和电重塑反应，评估对收缩功能和心率调节的功能影响，并确定潜在机制。进一步的创新在于解决 CF 到 CM 交叉调节在综合重塑响应中的作用。拟议的研究意义重大，因为我们将获得关于 CF 中 Gq 介导的信号传导、其调节以及对 CF、CM 及其综合重塑反应的后果的新见解，预计将有助于开发针对心脏重塑的新策略心力衰竭的治疗/预防。

项目成果

Cardiac overexpression of constitutively active Galpha q causes angiotensin II type1 receptor activation, leading to progressive heart failure and ventricular arrhythmias in transgenic mice.

心脏中持续活跃的 Galpha q 过度表达会导致血管紧张素 II 1 型受体激活，从而导致转基因小鼠出现进行性心力衰竭和室性心律失常。

• 发表时间: 2014
• 影响因子: 3.7
• 作者: Matsushita, Naoko;Kashihara, Toshihide;Shimojo, Hisashi;Suzuki, Satoshi;Nakada, Tsutomu;Takeishi, Yasuchika;Mende, Ulrike;Taira, Eiichi;Yamada, Mitsuhiko;Sanbe, Atsushi;Hirose, Masamichi
• 通讯作者: Hirose, Masamichi