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.

心脏收缩功能障碍引起的心力衰竭是一种流行病，影响超过500万人 美国的病人。虽然目前的治疗方法提高了生存率并减少了住院率，但这种疾病 持续以至少部分地由于细胞的收缩而导致的心肌收缩力的进行性降低为特征， 肥大、凋亡和细胞外基质重塑。G蛋白偶联受体的激活 （GPCR）-特别是β-肾上腺素能受体-在心脏的初始反应中起重要作用， 损伤以及为介导蛋白质级联的激活提供重要信号 适应不良性重塑在过去的二十年里，我们的实验室一直专注于G蛋白的作用， 信号和下游信号通过肿瘤坏死因子-a（TNF）对适应不良的重塑， 心与β-肾上腺素能信号相比，已经提出配体腺苷及其同源物 GPCR，在心脏应激期间保护心脏免受损伤。四种已知的腺苷受体亚型（A1， A2 A-、A2 B-和A3-R）已被鉴定并以组织特异性方式表达。事实上， 这些受体抑制TNF表达并限制肾上腺素能信号传导。然而，特异性腺苷受体 亚型激活具有完全相反作用的途径：A-、-和A3-R抑制腺苷酸 A2 A-Rs通过激活Gs激活腺苷酸环化酶，而A2 A-Rs通过激活Gs激活腺苷酸环化酶。早期 评估这些选择性腺苷受体亚型在心脏生理学中的作用的研究， 病理生理学受到缺乏真正“选择性”亚型特异性激动剂或拮抗剂的限制。 然而，很好地描述了腺苷水平在缺血心脏中增加，并且使用转基因的研究表明， 其中受体组成型表达或消除的小鼠模型证明Ar和A3- Rs是缺血/再灌注期间心脏保护的关键介质。 重要的是，我们实验室最近的研究使用转基因小鼠模型，其中转基因 表达可以“控制”导致了对当前教条的重新评估， 心脏中的选择性腺苷受体，特别是它们在心脏损伤和修复过程中的作用。这些 研究表明：1）与缺血心肌中的腺苷水平相比， 在衰竭的鼠心脏中水平显著降低; 2）组成性和受控的过表达 ArR导致心力衰竭的发展; 3）A^-R的组成性和受控的过度表达 增强心肌收缩力，而不发展细胞肥大;和4）过表达 A2 A-R可预防过表达ArR的小鼠的心力衰竭表型。我们的初步数据还 表明心脏中A^-R信号和β-肾上腺素能信号作用的显著差异 可能是由于通过Akt（蛋白激酶B）对下游信号传导的受体亚型特异性作用， GRK 5和G|.此外，Ar和A^-R信号在心脏中的不同作用似乎是由于 对肌浆网处理钙（Ca 2+）的不同影响。总的来说，这些结果 使我们假设单个腺苷受体亚型在心脏信号传导中发挥独特作用 在正常心脏生理过程中以及在对引起心脏损害的应激源的生理反应中， 损伤和进展为心力衰竭。如果为真，该假设对正在进行的临床试验具有重要的安全性意义。 评估多种腺苷受体亚型特异性激动剂在人体中的功效的研究， 对手。 为了验证这一假设，我们将追求三个特定的目标，以测试是否：1）A^-R介导的 信号传导对心肌生理学具有独特的作用， 通过不同的信号通路支持; 2）细胞内Ca 2+处理的变化改变了心脏 腺苷受体过表达后的表型;和3）通过G、GRK 5和/或GRK 5的下游信号传导 Akt调节心脏中AaA-R信号传导的适应性效应。这些研究将由 在我们自己的实验室开发的独特模型，基因转移技术，外科专业知识和先进的 通过核心设施提供的成像，以及在Ca 2+稳态和GPCR信号传导方面的专业知识， 在我们的PPG团队中。