Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure

Hiroyuki Nakayama, Xiongwen Chen, Christopher P. Baines, Raisa Klevitsky, Xiaoying Zhang, Hongyu Zhang, Naser Jaleel, Balvin H.L. Chua, Timothy E. Hewett, Jeffrey Robbins, Steven R. Houser, Jeffery D. Molkentin

Research output: Contribution to journalArticle

286 Scopus citations

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 β-adrenergic receptors. Enhanced Ca2+ influx-induced cellular necrosis and cardiomyopathy was prevented with either LTCC blockers or β-adrenergic receptor antagonists, demonstrating a proximal relationship among β-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 β-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 β-adrenergic receptor signaling.

Original languageEnglish (US)
Pages (from-to)2431-2444
Number of pages14
JournalJournal of Clinical Investigation
Volume117
Issue number9
DOIs
StatePublished - Sep 4 2007

ASJC Scopus subject areas

  • Medicine(all)

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    Nakayama, H., Chen, X., Baines, C. P., Klevitsky, R., Zhang, X., Zhang, H., Jaleel, N., Chua, B. H. L., Hewett, T. E., Robbins, J., Houser, S. R., & Molkentin, J. D. (2007). Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure. Journal of Clinical Investigation, 117(9), 2431-2444. https://doi.org/10.1172/JCI31060