title: β2-adrenergic receptors mediate cardioprotection through crosstalk with mitochondrial cell death pathways.
abstract: β-adrenergic receptors (β-ARs) modulate cardiotoxicity/cardioprotection through crosstalk with multiple signaling pathways. We have previously shown that β2-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 β2-AR to regulators of mitochondrial function are not clear. The objective of this study was to assess mechanisms of crosstalk between β2-ARs and mitochondrial cell death pathways. DOX administered to WT mice resulted in no acute mortality, however 85% of β2-/- mice died within 30 min. Several pro- and anti-survival pathways were altered. The pro-survival kinase, εPKC, was decreased by 64% in β2-/- after DOX vs WT (p<0.01); the εPKC activator ψεRACK partially rescued these mice (47% reduction in mortality). Activity of the pro-survival kinase Akt decreased by 76% in β2-/- after DOX vs WT (p<0.01). The α1-antagonist prazosin restored Akt activity to normal and also partially reversed the mortality (45%). Deletion of the β2-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 β2-/- (26%). Mitochondrial architecture was disrupted and complex I and II activities decreased by 40.9% and 34.6% respectively after DOX only in β2-/-. The MPT blocker cyclosporine reduced DOX mortality by 41% and prazosin plus cyclosporine acted synergistically to decrease mortality by 85%. β2-ARs activate pro-survival kinases and attenuate mitochondrial dysfunction during oxidative stress; absence of β2-ARs enhances cardiotoxicity via negative regulation of survival kinases and enhancement of intracellular Ca(2+), thus predisposing the mitochondria to opening of the MPT.
authors.affiliation: Department of Pediatrics (Cardiology), Stanford University, Stanford, CA, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fajardo
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhao
authors.forename: Gerald
authors.initials: G
authors.lastname: Berry
authors.forename: Lee-Jun
authors.initials: LJ
authors.lastname: Wong
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D009202:Cardiomyopathies / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology; D016572:Cyclosporine / Q000494:pharmacology; D004317:Doxorubicin / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D011224:Prazosin / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015996:Survival Rate; D014700:Verapamil / Q000494:pharmacology
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018343:Receptors, Adrenergic, beta-2; D004317:Doxorubicin; D016572:Cyclosporine; D014700:Verapamil; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium; D011224:Prazosin