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 6

Dox-induced shut-off of the β2a transgene prevents disease.

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Dox-induced shut-off of the β2a transgene prevents disease. (A) Gross mo...
(A) Gross morphological pictures of high-expressing DTG β2a mice without Dox treatment (No Dox; induced) or with Dox (shut off) at 14 weeks of age. (B) Heart weight normalized to body weight and (C) fractional shortening in high-expressing DTG mice without Dox or with Dox. Numbers indicate the number of mice analyzed in each group. *P < 0.05 versus DTG without Dox, Student’s t test. (D) Kaplan-Meier curves of control tTA single-transgenic and low-expressing DTG mice infused with Iso at 60 mg/kg/d for 14 days or with PBS vehicle. Low-expressing DTG mice were given Dox for 2 weeks prior to shut off β2a expression. (E) Fractional shortening in control tTA single-transgenic and low-expressing DTG mice pretreated with Dox for 2 weeks; some were given 14 days of Iso treatment. Numbers indicate the number of mice analyzed in each group. Data were analyzed by ANOVA. (F) Histological assessment of cardiac ventricular pathology by Masson’s trichrome in control tTA single-transgenic and low-expressing DTG mice with PBS or Iso infusion for 14 days with 2 weeks of prior Dox treatment. (G) Histological assessment of Ca2+ deposits in myocytes by von Kossa staining in control tTA single-transgenic and low-expressing DTG mice with PBS or Iso infusion for 14 days with 2 weeks of prior Dox treatment.