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.
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