Source Paper
Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure
Hiroyuki Nakayama, Xiongwen Chen, et al.
Source Paper
Hiroyuki Nakayama, Xiongwen Chen, et al.
Journal of Clinical Investigation • 2007
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.
Objective: Assessment of progressive myocyte necrosis, pump dysfunction, and survival in inducible transgenic mice with enhanced sarcolemmal L-type Ca2+ channel activity, and evaluation of mechanisms underlying Ca2+-dependent cardiomyocyte necrosis in heart failure
Inducible transgenic mice with enhanced sarcolemmal L-type Ca2+ channel activity were generated and maintained
Note: Mice were inducible transgenic models designed to express enhanced LTCC activity
“Inducible transgenic mice with enhanced sarcolemmal L-type Ca2+ channel (LTCC) activity showed progressive myocyte necrosis”
Progressive myocyte necrosis was assessed in transgenic mice with enhanced LTCC activity
Note: Necrosis was evaluated as a primary outcome measure
“Inducible transgenic mice with enhanced sarcolemmal L-type Ca2+ channel (LTCC) activity showed progressive myocyte necrosis that led to pump dysfunction”
Cardiac pump dysfunction was assessed as a consequence of myocyte necrosis
Note: Pump dysfunction was measured as a secondary outcome
“progressive myocyte necrosis that led to pump dysfunction and premature death”
Acute stimulation of β-adrenergic receptors was applied to enhance the phenotype
Note: Effects were dramatically enhanced by acute stimulation of β-adrenergic receptors
“effects that were dramatically enhanced by acute stimulation of β-adrenergic receptors”
L-type Ca2+ channel blockers were administered to test prevention of necrosis and cardiomyopathy
Note: LTCC blockers prevented enhanced Ca2+ influx-induced cellular necrosis and cardiomyopathy
“Enhanced Ca2+ influx-induced cellular necrosis and cardiomyopathy was prevented with either LTCC blockers”
β-adrenergic receptor antagonists were administered to test prevention of necrosis and cardiomyopathy
Note: β-adrenergic antagonists prevented enhanced Ca2+ influx-induced cellular necrosis and cardiomyopathy
“Enhanced Ca2+ influx-induced cellular necrosis and cardiomyopathy was prevented with either LTCC blockers or β-adrenergic receptor antagonists”
Transgenic mice with loss of cyclophilin D were evaluated to determine its role in necrosis regulation
Note: Cyclophilin D is a regulator of the mitochondrial permeability transition pore that underpins necrosis
“loss of cyclophilin D, a regulator of the mitochondrial permeability transition pore that underpins necrosis, blocked Ca2+ influx-induced necrosis”
Transgenic mice with Bcl-2 overexpression were evaluated to test antiapoptotic factor effectiveness
Note: Bcl-2 overexpression was ineffective in mitigating heart failure and death associated with excess Ca2+ influx
“overexpression of the antiapoptotic factor Bcl-2 was ineffective in mitigating heart failure and death associated with excess Ca2+ influx”
Isoproterenol was used to induce acute β-adrenergic receptor stimulation and assess survival outcomes
Note: Isoproterenol-induced premature death was prevented by loss of cyclophilin D
“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”
The paradigm of mitochondrial- and necrosis-dependent heart failure was evaluated in other mouse models of disease
Note: Results were validated across multiple disease models
“This paradigm of mitochondrial- and necrosis-dependent heart failure was also observed in other mouse models of disease”
Inducible transgenic mice with enhanced sarcolemmal L-type Ca2+ channel (LTCC) activity; also included transgenic mice with loss of cyclophilin D and Bcl-2 overexpression variants