b1-/b2-Adrenergic Receptor Mechanisms in Cardiomyocytes

描述（由申请人提供）：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起着复杂的（有些矛盾的）作用。 在短期内，β-肾上腺素能受体（b-AR）的儿茶酚胺激活增加了收缩力和心率，并提供了一种强大的代偿机制来维持心输出量。 然而，随着时间的推移，慢性持续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。 心肌细胞中的儿茶酚胺作用传统上归因于通过传统cAMP/蛋白激酶A途径起作用的β 1-AR亚型。 然而，最近的研究表明，心肌细胞共表达β 2-AR，其提供了变力性支持的替代来源，并且还影响缺血应激期间的心肌细胞生长和存活，β 2-AR应答在心力衰竭中变得特别重要，其中β 1-AR下调。 重要的是，b1-和b2-AR在未分化细胞系中异源表达时具有非常相似的信号表型，但高度分化的心肌细胞中的天然b1-和b2-AR具有不同的信号特性。 B- AR亚型与效应物（与cAMP途径和b-AR的非传统靶点，如促分裂原活化蛋白激酶级联、磷酸肌醇-3激酶/AKT和酪氨酸激酶）偶联的差异是它们在心脏中独特生物学作用的基础。 最近的研究确定了靶向膜亚结构域（脂筏/小窝）的b-AR亚型的差异，作为调节其进入下游效应物的机制。 本申请的目的是（I）开发对由心肌细胞b1-和b2-AR激活的不同分子途径及其在慢性心力衰竭发病机制中的作用的更精确理解，（II）定义决定小窝中的b2-AR和其它表面膜中的b1-AR的亚型特异性区室化的结构域，和（III）确定区室化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，这些研究将定义区分心肌细胞中b1-和b2-AR作用的分子机制。 因此，这些研究可能会提出新的临床策略，可以追求（或应该避免）的管理慢性心力衰竭的人。

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.