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
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
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Research Article Cardiology

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 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.

Authors

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

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Figure 10

Loss of cyclophilin D rescues disease in β2a-overexpressing mice.

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Loss of cyclophilin D rescues disease in β2a-overexpressing mice. (A) Gr...
(A) Gross morphological view of hearts from a DTG mouse and a DTG mouse lacking Ppif without Dox (4 months of age). (B–E) Heart weight normalized to body weight (B), fractional shortening assessment (C), histological assessment of cardiac pathology by Masson’s trichrome staining (D), and quantitation of fibrotic area (blue) from trichrome-stained cardiac histological sections (E) for control tTA single-transgenic, DTG, Ppif–/–, and DTG Ppif–/– mice. Numbers indicate the number of mice analyzed in each group (E, 10 photographs each). Original magnification, ×200 (D). *P < 0.05 versus control; #P < 0.05 versus DTG, ANOVA. (F) Kaplan-Meier curves from control tTA single-transgenic mice, Ppif–/– mice, and DTG mice with or without Ppif infused with Iso at 60 mg/kg/d for 14 days. (G) Ca2+ current at different test potentials from adult myocytes isolated from DTG mice (n = 9) or DTG Ppif–/– mice (n = 8). Both show equivalently high currents compared with control wild-type cells shown in Figure 2A.