b1-/b2-Adrenergic Receptor Mechanisms in Cardiomyocytes

描述(申请人提供)：心力衰竭是许多常见心脏疾病(高血压、冠状动脉疾病、心肌病)的最终共同终点；它已成为美国和其他发达国家发病率和死亡率的主要原因。儿茶酚胺在慢性心力衰竭的发病机制中扮演着复杂的(有些自相矛盾的)角色。在短期内，b-肾上腺素能受体(b-ARs)的儿茶酚胺激活可增加收缩能力和心率，并为维持心输出量提供强大的代偿机制。然而，随着时间的推移，长期无情的儿茶酚胺刺激会加速心力衰竭的自然病程；血浆去甲肾上腺素水平是公认的心力衰竭死亡率的预后指标。儿茶酚胺在心肌细胞中的作用传统上归因于β1-AR亚型通过传统的cAMP/蛋白激酶A途径发挥作用。然而，最近的研究表明，心肌细胞共表达b2-AR，提供另一种肌力支持来源，并在缺血应激期间影响心肌细胞的生长和存活，b2-AR反应在心力衰竭中变得尤为重要，其中β1-AR下调。重要的是，b1-和b2-AR在未分化的细胞系中异源表达时具有非常相似的信号表型，但在高分化的心肌细胞中天然的b1-和b2-AR具有不同的信号特性。B-AR亚型与效应物(cAMP途径和b-Ars的非传统靶点，如丝裂原活化蛋白激酶级联、肌醇磷脂-3激酶/AKT和酪氨酸激酶)偶联的不同，是它们在心脏中不同生物学作用的基础。最近的研究发现，b-AR亚型靶向膜亚结构域(脂筏/小窝)的差异是调节它们进入下游效应器的一种机制。这项应用的目的是(I)更准确地了解心肌细胞b1-和b2-AR激活的不同分子通路及其在慢性心力衰竭发病机制中的作用，(Ii)确定决定b2-AR在小窝中和b1-AR在其他表膜中的亚型特异性区隔的结构域，以及(Iii)确定区隔作为区分心肌细胞中b1和b2-AR作用的机制的功能重要性。总的来说，这些研究将确定区分b1和b2受体在心肌细胞中作用的分子机制。因此，这些研究可能会提出新的临床策略，可能会被追求(或应该避免)来管理人类的慢性心力衰竭。

DESCRIPTION (provided by applicant): Heart failure represents the final common end point of many common cardiac disorders (hypertension, coronary artery disease, cardiomyopathy); it has become a leading cause of morbidity and mortality in the US and other developed nations. Catecholamines play a complex (and somewhat paradoxical) role in the pathogenesis of chronic cardiac failure. In the short term, catecholamine activation of b-adrenergic receptors (b-ARs) increases contractility and heart rate and provides a powerful compensatory mechanism to maintain cardiac output. However, over time, chronic unrelenting catecholamine stimulation accelerates the natural history of heart failure; plasma norepinephrine levels are a well-recognized prognostic indicator of heart failure mortality. Catecholamine actions in cardiomyocytes traditionally have been attributed to the beta1-AR subtype acting via the traditional cAMP/protein kinase A pathway. However, recent studies indicate that cardiomyocytes co-express b2-ARs that provide an alternate source of inotropic support and also influence cardiomyocyte growth and survival during ischemic stresses, b2-AR responses become particularly important in heart failure, where beta 1-ARs are down-regulated. Importantly, b1- and b2-ARs have very similar signaling phenotypes when heterologously expressed in undifferentiated cell lines, but the native b1- and b2-ARs in highly differentiated cardiomyocytes have distinct signaling properties. Differences in b- AR subtype coupling to effectors (both to the cAMP pathway and non-traditional targets of b-ARs, such as mitogen-activated protein kinase cascades, phosphoinositide-3 kinase/AKT, and tyrosine kinases) underlie their distinct biological actions in the heart. Recent studies identify differences in b-AR subtype targeting to membrane subdomains (lipid rafts/caveolae) as a mechanism to regulate their access to downstream effectors. The goals of this application are to (I) develop a more precise understanding of the distinct molecular pathways activated by cardiomyocyte b1- and b2-ARs and their role in the pathogenesis of chronic cardiac failure, (II) define the structural domains that dictate subtype-specific compartmentation of b2-ARs in caveolae and b1-ARs in other surface membranes, and (III) determine the functional importance of compartmentation as a mechanism to distinguish b1- and b2-AR actions in cardiomyocytes. Collectively, these studies will define the molecular mechanisms that distinguish b1- and b2-AR actions in cardiomyocytes. As such, these studies are likely to suggest novel clinical strategies that might be pursued (or should be avoided) for the management of chronic heart failure in humans.