Role of Adenosine Receptors in Cardiac Failure and Protection

腺苷受体在心力衰竭和保护中的作用

• 批准号: 7488121
• 负责人: ARTHUR M FELDMAN
• 金额: $ 49.93万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7488121
• 关键词: Adenosine; Adenylate Cyclase; Adrenergic Agents; Adrenergic Receptor; Affect; Agonist; Apoptosis; Calcium; Cardiac; Cardiovascular Physiology; Cardiovascular system; Clinical Research; Core Facility; Data; Development; Disease; Epidemic; Extracellular Matrix; Family; Functional disorder; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GRK5 gene; GTP-Binding Proteins; Gene Transfer; Goals; Heart; Heart failure; Homeostasis; Hospitalization; Human; Hypertrophy; Image; Individual; Infarction; Inflammatory Response; Injury; Ischemia; Laboratories; Ligands; Mediating; Mediator of activation protein; Modeling; Mus; Myocardial; Myocardial Ischemia; Myocardium; Norepinephrine; Operative Surgical Procedures; Pathway interactions; Patients; Personal Satisfaction; Phenotype; Physiological; Physiological reperfusion; Physiology; Play; Process; Protein Overexpression; Proteins; Proto-Oncogene Proteins c-akt; Purine Nucleosides; Purinergic P1 Receptors; Reagent; Receptor Activation; Reperfusion Therapy; Role; Safety; Sarcoplasmic Reticulum; Secondary to; Signal Pathway; Signal Transduction; Signaling Molecule; Stress; Technology; Testing; Tissues; Transgenic Model; Transgenic Organisms; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Work; adenosine receptor activation; adrenergic; human TNF protein; improved; injury and repair; member; mouse model; novel strategies; prevent; receptor; response; size; stressor; tool; transgene expression

Heart failure due to systolic dysfunction is a disease of epidemic proportions affecting over 5 million patients in the US. Although present treatments improve survival and decrease hospitalizations, the disease continues to be characterized by a progressive decrease in cardiac contractility due at least in part to cellular hypertrophy, apoptosis and extracellular matrix remodeling. Activation of G protein-coupled receptors (GPCRs) - in particular the (3-adrenergic receptors -plays a significant role in the heart's initial response to damage as well as providing important signals for activation of the cascade of proteins that mediate maladaptive remodeling. Over the past two decades, our laboratory has focused on the role of G protein signaling and downstream signaling through tumor necrosis factor-a (TNF) on maladaptive remodeling in the heart. By contrast with (3-adrenergic signaling, it has been proposed that the ligand adenosine and its cognate GPCRs, protect the heart against injury during cardiac stress. Four known adenosine receptor subtypes (A^, A2A-, A2B-, and A3-R's) have been identified and are expressed in a tissue specific fashion. Indeed, activation of these receptors inhibits TNF expression and limits adrenergic signaling. However, specific adenosine receptor subtypes activate pathways that have diametrically opposite effects: The A-,-, and A3-Rs inhibit adenylyl cyclase through activation of Gj, whereas the A2A-Rs activate adenylyl cyclase through activation of Gs. Early studies assessing the role of these selective adenosine receptor subtypes in cardiac physiology and pathophysiology were limited by the absence of truly "selective" sub-type specific agonists or antagonists. However, it is well described that adenosine levels increase in the ischemic heart and studies using transgenic mouse models in which the receptors are constitutively expressed or ablated demonstrate that the Ar and A3- Rs are key mediators of cardioprotection during ischemia/reperfusion. Importantly, recent studies from our laboratory using transgenic mouse models in which transgene expression can be "controlled" have resulted in a reassessment of the current dogma regarding the role of selective adenosine receptors in the heart and in particular their role during cardiac injury and repair. These studies have demonstrated that: 1) by contrast with adenosine levels in ischemic myocardium, adenosine levels decrease substantially in the failing murine heart; 2) both constitutive and controlled overexpression of the ArR results in the development of heart failure; 3) constitutive and controlled overexpression of the A^-R enhances cardiac contractility without the development of cellular hypertropohy; and 4) overexpression of the A2A-R prevents the heart failure phenotype in mice overexpressing the ArR. Our preliminary data also suggests that the marked differences in the effects of A^-R signaling and (3-adrenergic signaling in the heart might be due to receptor sub-type specific effects on downstream signaling through Akt (protein kinase B), GRK5 and G|. Furthermore, the disparate effects of Ar and A^-R signaling in the heart appear to be due to disparate effects on calcium (Ca2+) handling by the sarcoplasmic reticulum. Taken together, these results have led us to hypothesize that the individual adenosine receptor subtypes play unique roles in cardiac signaling and function during normal cardiac physiology and in the physiologic response to stressors that cause cardiac injury and progress to heart failure. If true, this hypothesis has important safety implications for ongoing clinical studies assessing the efficacy in humans of a variety of adenosine receptor sub-type specific agonists and antagonists. To test this hypothesis we will pursue three Specific Aims that will test whether: 1) A^-R-mediated signaling has unique effects on myocardial physiology and affords both cardiac protection and inotropic support through distinct signaling pathways; 2) changes in intracellular Ca2+ handling modifies the cardiac phenotype after overexpression of adenosine receptors; and 3) downstream signaling through G, GRK5 and/or Akt modulates the adaptive effects of AaA-R signaling in the heart. These studies will be facilitated by the unique models developed in our own laboratory, gene transfer technology, surgical expertise and sophisticated imaging available through the Core facilities, and the expertise in Ca2+ homeostasis and GPCR signaling that is present within our PPG group.

由于收缩功能障碍引起的心力衰竭是一种流行比例的疾病，影响超过500万 美国的患者。尽管目前的治疗可改善生存率并减少住院治疗，但该疾病 继续以逐渐降低心脏收缩性的特征，至少部分归因于细胞 肥大，凋亡和细胞外基质重塑。 G蛋白偶联受体的激活 （GPCRS） - 特别是（3-肾上腺素受体 - 在心脏对心脏的初始反应中起着重要作用 损害以及提供重要的信号，以激活介导的蛋白质级联 适应不良的重塑。在过去的二十年中，我们的实验室专注于G蛋白的作用 通过肿瘤坏死因子-A（TNF）的信号传导和下游信号传导在适应不良重塑中的信号传导和信号传导 心。与（3-肾上腺素信号传导相比，已经提出配体腺苷及其同源 GPCR，保护心脏在心脏应激期间免受损伤。四个已知的腺苷受体亚型（A^， 已经鉴定出A2A-，A2B-和A3-R），并以特定于组织的方式表达。确实，激活 这些受体抑制TNF表达，并限制肾上腺素能信号传导。但是，特定的腺苷受体 亚型激活具有截然相反作用的途径：a - ， - 和a3-rs抑制腺苷酸 通过激活GJ的循环酶，而A2A-RS通过激活GS激活腺苷酸环化酶。早期的 评估这些选择性腺苷受体亚型在心脏生理学和 病理生理学受到真正的“选择性”亚型特异性激动剂或拮抗剂的限制。 但是，有充分描述的是，腺苷水平在缺血性心脏中升高，并使用转基因进行研究 组成型表达或消融受体的小鼠模型表明AR和A3- RS是缺血/再灌注过程中心脏保护的关键介体。 重要的是，我们实验室的最新研究使用转基因小鼠模型，其中转基因 表达可以被“控制”导致对当前教条的重新评估 选择性腺苷受体在心脏中，尤其是它们在心脏损伤和修复中的作用。这些 研究表明：1）与缺血性心肌中的腺苷水平相反 失败的鼠心脏中的水平大大降低； 2）构成和受控的过表达 ARR导致心力衰竭的发展； 3）A^-R的组成型和控制的过表达 增强心脏收缩性，而不会发展细胞高纤维。 4）过表达 A2A-R防止过表达ARR的小鼠的心力衰竭表型。我们的初步数据 表明A^-R信号和（心脏3-肾上腺素能信号传导的效果的明显差异） 可能是由于受体亚型特异性对下游信号的特异性影响（蛋白激酶B）， grk5和g |。此外，心脏中AR和A^-R信号的不同作用似乎是由于 肌质网对钙（Ca2+）处理的不同影响。综上所述，这些结果有 导致我们假设单个腺苷受体亚型在心脏信号中起着独特的作用 在正常心脏生理和对压力源的生理反应中的功能和功能 受伤和心力衰竭的进展。如果是真的，该假设对正在进行的临床具有重要的安全性影响 评估各种腺苷受体亚型特异性激动剂和人类功效的研究 对手。 为了检验这一假设 信号传导对心肌生理具有独特的影响，并提供心脏保护和肌力保护 通过不同的信号通路支撑； 2）细胞内Ca2+处理的变化会改变心脏 腺苷受体过表达后的表型； 3）通过G，GRK5和/或 AKT调节心脏中AAA-R信号的适应性效应。这些研究将由 在我们自己的实验室，基因转移技术，外科专业知识和复杂的独特模型中开发的独特模型 通过核心设施可用的成像，以及CA2+稳态和GPCR信号的专业知识是 存在于我们的PPG组中。