Chronic activation of the sympathetic nervous system plays an important role in the pathogenesis of dilated cardiomyopathy, leading to the selective downregulation of b1-adrenoceptors (ARs), but usually sparing the b2-subtype. Restoration of normal b-AR signaling has therefore been the basis for pharmacologic therapies of cardiomyopathy. However, there is considerable heterogeneity between pi and b2-ARs beyond their different ligand affinities, with some evidence suggesting that b1-AR signaling may be cardiotoxic whereas b2-AR signaling may be cardioprotective. We have generated compelling data in the mouse suggesting a differential role for b1 and b2-AR subtypes in mediating a toxic cardiomyopathy, due to the anthracycline doxorubicin. Wildtype mice receiving a single therapeutic dose of doxorubicin do not manifest any acute toxicity. In contrast, b2-AR knockout (b2-/-) mice have markedly enhanced cardiotoxicity and die within 30 min. The additional deletion of the b1-AR (b1/b2-/- mice) rescues this enhanced toxicity. This effect is recapitulated in cells from knockout mice and partially recapitulated using b-AR subtype-specific antagonists (with some interesting differences). In contrast, when doxorubicin is given at a lower dose in a model of chronic toxicity, lack of the b2-AR confers cardioprotection! There is no other model where manipulation of one b-AR subtype results in such a profound effect on function and survival. This severe phenotype suggests activation of potentially novel signaling events by b-AR subtypes. Preliminary data suggest that cross-talk with signaling pathways such as MARK, PKC and Akt could contribute to this phenotype, as well as alterations in Ca2+ homeostasis interacting with mitochondrial pathways of cell energetics and cell death. The overall aim of this proposal is to determine the mechanisms for both subtype-specific and temporal- specific b-AR mediation of cardiotoxicity and cardioprotection. We utilize doxorubicin as a model to determine how b-AR subtypes regulate cardiotoxicity/cardioprotection: 1) through crosstalk with signaling pathways mediating cell death, survival and remodeling (PKC, MAPK, Akt, ROS) as well as signaling mediated by b-AR scaffolding domains; 2) through alterations in intracellular and intramitochondrial Ca homeostasis and crosstalk with mitochondrial pathways regulating cellular energetics and cell death (MPT, KATP channel activation, PARP) and 3) through alterations in gene expression, using a genome-wide screen to examine both classical and novel signaling pathways. Developing a better understanding of the role of b-AR subtypes in cardiotoxic/cardioprotective signaling has therapeutic consequences for cardiomyopathies in general: if b1-ARs are toxic and b2-ARs are protective, as some have suggested, then future therapy of heart failure could be tailored to address these receptor- specific effects. However, our data suggest that the intricacies of b-AR subtype signaling, the temporal dependence of this signaling, and the multiple pathways of potential crosstalk, are quite a bit more complex. ? ? ? ? ?
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