title: Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure.
abstract: Loss of cardiac myocytes in heart failure is thought to occur largely through an apoptotic process. Here we show that heart failure can also be precipitated through myocyte necrosis associated with Ca2+ overload. Inducible transgenic mice with enhanced sarcolemmal L-type Ca2+ channel (LTCC) activity showed progressive myocyte necrosis that led to pump dysfunction and premature death, effects that were dramatically enhanced by acute stimulation of beta-adrenergic receptors. Enhanced Ca2+ influx-induced cellular necrosis and cardiomyopathy was prevented with either LTCC blockers or beta-adrenergic receptor antagonists, demonstrating a proximal relationship among beta-adrenergic receptor function, Ca2+ handling, and heart failure progression through necrotic cell loss. Mechanistically, loss of cyclophilin D, a regulator of the mitochondrial permeability transition pore that underpins necrosis, blocked Ca2+ influx-induced necrosis of myocytes, heart failure, and isoproterenol-induced premature death. In contrast, overexpression of the antiapoptotic factor Bcl-2 was ineffective in mitigating heart failure and death associated with excess Ca2+ influx and acute beta-adrenergic receptor stimulation. This paradigm of mitochondrial- and necrosis-dependent heart failure was also observed in other mouse models of disease, which supports the concept that heart failure is a pleiotropic disorder that involves not only apoptosis, but also necrotic loss of myocytes in association with dysregulated Ca2+ handling and beta-adrenergic receptor signaling.
authors: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors: Hiroyuki
authors: H
authors: Nakayama
authors: Xiongwen
authors: X
authors: Chen
authors: Christopher P
authors: CP
authors: Baines
authors: Raisa
authors: R
authors: Klevitsky
authors: Xiaoying
authors: X
authors: Zhang
authors: Hongyu
authors: H
authors: Zhang
authors: Naser
authors: N
authors: Jaleel
authors: Balvin H L
authors: BH
authors: Chua
authors: Timothy E
authors: TE
authors: Hewett
authors: Jeffrey
authors: J
authors: Robbins
authors: Steven R
authors: SR
authors: Houser
authors: Jeffery D
authors: JD
authors: Molkentin
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D009336:Necrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D020746:Calcium Channels, L-Type; D056741:Cyclin D; D016213:Cyclins; D018343:Receptors, Adrenergic, beta-2; D002118:Calcium
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