Abstract

ß-adrenergic receptors (ß-ARs) modulate cardiotoxicity/cardioprotection through crosstalk with multiple signaling pathways. We have previously shown that ß2-ARs are cardioprotective during exposure to oxidative stress induced by doxorubicin (DOX). DOX cardiotoxicity is mediated in part through a Ca(2+)-dependent opening of the mitochondrial permeability transition (MPT), however the signals linking a cell surface receptor like the ß2-AR to regulators of mitochondrial function are not clear. The objective of this study was to assess mechanisms of crosstalk between ß2-ARs and mitochondrial cell death pathways. DOX administered to WT mice resulted in no acute mortality, however 85% of ß2-/- mice died within 30 min. Several pro- and anti-survival pathways were altered. The pro-survival kinase, ePKC, was decreased by 64% in ß2-/- after DOX vs WT (p<0.01); the ePKC activator ?eRACK partially rescued these mice (47% reduction in mortality). Activity of the pro-survival kinase Akt decreased by 76% in ß2-/- after DOX vs WT (p<0.01). The a1-antagonist prazosin restored Akt activity to normal and also partially reversed the mortality (45%). Deletion of the ß2-AR increased rate of Ca(2+) release by 75% and peak [Ca(2+)](i) by 20% respectively in isolated cardiomyocytes; the Ca(2+) channel blocker verapamil also partially rescued the ß2-/- (26%). Mitochondrial architecture was disrupted and complex I and II activities decreased by 40.9% and 34.6% respectively after DOX only in ß2-/-. The MPT blocker cyclosporine reduced DOX mortality by 41% and prazosin plus cyclosporine acted synergistically to decrease mortality by 85%. ß2-ARs activate pro-survival kinases and attenuate mitochondrial dysfunction during oxidative stress; absence of ß2-ARs enhances cardiotoxicity via negative regulation of survival kinases and enhancement of intracellular Ca(2+), thus predisposing the mitochondria to opening of the MPT.

View details for DOI 10.1016/j.yjmcc.2011.06.019

View details for PubMedID 21756913