β2-adrenergic receptors mediate cardioprotection through crosstalk with mitochondrial cell death pathways

beta-adrenergic receptors (beta-ARs) modulate cardiotoxicity/cardioprotection through crosstalk with multiple signaling pathways. We have previously shown that beta 2-ARs are cardioprotective during exposure to oxidative stress induced by doxorubicin (DOX). DOX cardiotoxicity is mediated in part through a Ca2+-dependent opening of the mitochondrial permeability transition (MPT), however the signals linking a cell surface receptor like the beta 2-AR to regulators of mitochondrial function are not clear. The objective of this study was to assess mechanisms of crosstalk between beta 2-ARs and mitochondrial cell death pathways. DOX administered to WT mice resulted in no acute mortality, however 85% of beta 2-/- mice died within 30 min. Several pro- and anti-survival pathways were altered. The pro-survival kinase, epsilon PKC, was decreased by 64% in beta 2-/- after DOX vs WT (p<0.01); the epsilon PKC activator psi epsilon RACK partially rescued these mice (47% reduction in mortality). Activity of the pro-survival kinase Akt decreased by 76% in beta 2-/- after DOX vs WT (p<0.01). The alpha 1-antagonist prazosin restored Akt activity to normal and also partially reversed the mortality (45%). Deletion of the beta 2-AR increased rate of Ca2+ release by 75% and peak [Ca2+](i) by 20% respectively in isolated cardiomyocytes: the Ca2+ channel blocker verapamil also partially rescued the beta 2-/- (26%). Mitochondrial architecture was disrupted and complex land II activities decreased by 40.9% and 34.6% respectively after DOX only in beta 2-/-. The MPT blocker cyclosporine reduced DOX mortality by 41% and prazosin plus cyclosporine acted synergistically to decrease mortality by 85%. beta 2-ARs activate pro-survival kinases and attenuate mitochondrial dysfunction during oxidative stress; absence of beta 2-ARs enhances cardiotoxicity via negative regulation of survival kinases and enhancement of intracellular Ca2+, thus predisposing the mitochondria to opening of the MPT. (C) 2011 Elsevier Ltd. All rights reserved.