Heart failure due to systolic dysfunction is a disease of epidemic proportions affecting over 5 millionpatients in the US. Although present treatments improve survival and decrease hospitalizations, the diseasecontinues to be characterized by a progressive decrease in cardiac contractility due at least in part to cellularhypertrophy, 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 todamage as well as providing important signals for activation of the cascade of proteins that mediatemaladaptive remodeling. Over the past two decades, our laboratory has focused on the role of G proteinsignaling and downstream signaling through tumor necrosis factor-a (TNF) on maladaptive remodeling in theheart. By contrast with (3-adrenergic signaling, it has been proposed that the ligand adenosine and its cognateGPCRs, 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 ofthese receptors inhibits TNF expression and limits adrenergic signaling. However, specific adenosine receptorsubtypes activate pathways that have diametrically opposite effects: The A-,-, and A3-Rs inhibit adenylylcyclase through activation of Gj, whereas the A2A-Rs activate adenylyl cyclase through activation of Gs. Earlystudies assessing the role of these selective adenosine receptor subtypes in cardiac physiology andpathophysiology 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 transgenicmouse 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 transgeneexpression can be 'controlled' have resulted in a reassessment of the current dogma regarding the role ofselective adenosine receptors in the heart and in particular their role during cardiac injury and repair. Thesestudies have demonstrated that: 1) by contrast with adenosine levels in ischemic myocardium, adenosinelevels decrease substantially in the failing murine heart; 2) both constitutive and controlled overexpression ofthe ArR results in the development of heart failure; 3) constitutive and controlled overexpression of the A^-Renhances cardiac contractility without the development of cellular hypertropohy; and 4) overexpression of theA2A-R prevents the heart failure phenotype in mice overexpressing the ArR. Our preliminary data alsosuggests that the marked differences in the effects of A^-R signaling and (3-adrenergic signaling in the heartmight 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 todisparate effects on calcium (Ca2+) handling by the sarcoplasmic reticulum. Taken together, these results haveled us to hypothesize that the individual adenosine receptor subtypes play unique roles in cardiac signalingand function during normal cardiac physiology and in the physiologic response to stressors that cause cardiacinjury and progress to heart failure. If true, this hypothesis has important safety implications for ongoing clinicalstudies assessing the efficacy in humans of a variety of adenosine receptor sub-type specific agonists andantagonists.To test this hypothesis we will pursue three Specific Aims that will test whether: 1) A^-R-mediatedsignaling has unique effects on myocardial physiology and affords both cardiac protection and inotropicsupport through distinct signaling pathways; 2) changes in intracellular Ca2+ handling modifies the cardiacphenotype after overexpression of adenosine receptors; and 3) downstream signaling through G, GRK5 and/orAkt modulates the adaptive effects of AaA-R signaling in the heart. These studies will be facilitated by theunique models developed in our own laboratory, gene transfer technology, surgical expertise and sophisticatedimaging available through the Core facilities, and the expertise in Ca2+ homeostasis and GPCR signaling that ispresent within our PPG group.
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