Role of Adenosine Receptors in Cardiac Failure and Protection

心脏收缩功能障碍引起的心力衰竭是一种流行疾病，影响着500多万人。 在美国的病人。尽管目前的治疗方法提高了存活率并减少了住院人数，但这种疾病 继续以心肌收缩能力进行性下降为特征，至少部分原因是细胞 肥大、细胞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-肾上腺素能受体)--在心脏的初始反应中发挥重要作用 损伤，并提供重要的信号激活级联的介导性蛋白质 适应不良的重塑。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 肿瘤坏死因子-a(TNF)在血管内皮细胞不良适应重塑中的信号和下游信号转导 心。通过与(3-肾上腺素能信号)的对比，提出了配体-腺苷及其同系物 GPCRs，在心脏应激期间保护心脏免受损伤。已知的四种腺苷受体亚型(A^， A2A-、A2B-和A3-R)已被鉴定，并以组织特异性方式表达。事实上，激活 这些受体抑制肿瘤坏死因子的表达，限制肾上腺素能信号转导。然而，特异性腺苷受体 亚型激活具有截然相反作用的通路：A-、-和A3-受体抑制腺苷 A2a-Rs通过激活Gs激活腺酰环化酶。早些时候 评估这些选择性腺苷受体亚型在心脏生理学和心脏功能中作用的研究 病理生理学受到缺乏真正的“选择性”亚型特定激动剂或拮抗剂的限制。 然而，已经很好地描述了缺血心脏中腺苷水平的增加，并使用转基因技术进行了研究 在受体结构性表达或消融的小鼠模型中，AR和A3- RS是缺血/再灌注过程中心脏保护的关键介质。 重要的是，我们实验室最近使用转基因小鼠模型进行的研究 表达可以被“控制”，这导致了对当前关于 心脏中的选择性腺苷受体，特别是它们在心脏损伤和修复中的作用。这些 研究表明：1)与缺血心肌中的腺苷水平相比，腺苷 在衰竭的小鼠心脏中水平显著下降；2)结构性和受控的过度表达 ARR导致心力衰竭的发展；3)A^-R的结构性和可控性过表达 在不发展细胞肥大的情况下增强心肌收缩能力；以及4)过表达 A2A-R可预防过度表达ARR的小鼠的心力衰竭表型。我们的初步数据也 提示心脏中A^-R信号和(3-肾上腺素能)信号作用的显著差异 可能是由于受体亚型通过Akt(蛋白激酶B)对下游信号的特定影响， GRK5和G|。此外，AR和A^-R信号在心脏中的不同影响似乎是由于 肌浆网对钙(钙)处理的不同影响。总而言之，这些结果有 这让我们假设，单个腺苷受体亚型在心脏信号中发挥着独特的作用 在正常心脏生理过程中和对引起心脏疾病的应激源的生理反应中 损伤和心力衰竭的进展。如果是真的，这一假设对正在进行的临床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对人体的疗效的研究 对抗者。 为了验证这一假设，我们将追求三个具体目标，以测试：1)A^-R介导 信号对心肌生理有独特的影响，并提供心脏保护和变力作用。 通过不同的信号通路提供支持；2)细胞内钙处理的变化改变心脏 腺苷受体过表达后的表型；3)通过G、GRK5和/或 AKT调节心脏AAA-R信号的适应效应。这些研究将由 我们在自己的实验室开发了独特的模型，基因转移技术，外科专业知识和尖端 通过核心设施提供的成像，以及在钙稳态和GPCR信号转导方面的专业知识 在我们的PPG小组中。

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.