Oxidative Stress in Dilated Cardiomyopathy Caused by MYBPC3 Mutation

Cardiomyopathies can result from mutations in genes encoding sarcomere proteins including MYBPC3, which encodes cardiac myosin binding protein-C (cMyBP-C). However, whether oxidative stress is augmented due to contractile dysfunction and cardiomyocyte damage in MYBPC3-mutated cardiomyopathies has not been elucidated. To determine whether oxidative stress markers were elevated in MYBPC3-mutated cardiomyopathies, a previously characterized 3-month-old mouse model of dilated cardiomyopathy (DCM) expressing a homozygous MYBPC3 mutation (cMyBP-C(t/t)) was used, compared to wild-type (WT) mice. Echocardiography confirmed decreased percentage of fractional shortening in DCM versus WT hearts. Histopathological analysis indicated a significant increase in myocardial disarray and fibrosis while the second harmonic generation imaging revealed disorganized sarcomeric structure and myocyte damage in DCM hearts when compared to WT hearts. Intriguingly, DCM mouse heart homogenates had decreased glutathione (GSH/GSSG) ratio and increased protein carbonyl and lipid malondialdehyde content compared to WT heart homogenates, consistent with elevated oxidative stress. Importantly, a similar result was observed in human cardiomyopathy heart homogenate samples. These results were further supported by reduced signals for mitochondrial semiquinone radicals and Fe-S clusters in DCM mouse hearts measured using electron paramagnetic resonance spectroscopy. In conclusion, we demonstrate elevated oxidative stress in MYPBC3-mutated DCM mice, which may exacerbate the development of heart failure.

[1]  Talicia Tarver,et al.  HEART DISEASE AND STROKE STATISTICS–2014 UPDATE: A REPORT FROM THE AMERICAN HEART ASSOCIATION , 2014 .

[2]  P. D. de Tombe,et al.  Contractile dysfunction in a mouse model expressing a heterozygous MYBPC3 mutation associated with hypertrophic cardiomyopathy. , 2014, American journal of physiology. Heart and circulatory physiology.

[3]  J. Eichorst,et al.  Imaging horse tendons using multimodal 2-photon microscopy. , 2014, Methods.

[4]  E. McNally,et al.  Genetic mutations and mechanisms in dilated cardiomyopathy. , 2013, The Journal of clinical investigation.

[5]  V. Adam,et al.  Redox status expressed as GSH:GSSG ratio as a marker for oxidative stress in paediatric tumour patients. , 2012, Oncology letters.

[6]  B. Paw,et al.  Cellular and mitochondrial iron homeostasis in vertebrates. , 2012, Biochimica et biophysica acta.

[7]  Lianfeng Zhang,et al.  Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnTR141W Dilated Cardiomyopathy Transgenic Mice , 2012, Hypertension.

[8]  Johannes E. Schindelin,et al.  Fiji: an open-source platform for biological-image analysis , 2012, Nature Methods.

[9]  Steven B Marston,et al.  How do MYBPC3 mutations cause hypertrophic cardiomyopathy? , 2012, Journal of Muscle Research and Cell Motility.

[10]  Arantxa González,et al.  New targets to treat the structural remodeling of the myocardium. , 2011, Journal of the American College of Cardiology.

[11]  Jean-Jacques Bellanger,et al.  Modeling of supramolecular centrosymmetry effect on sarcomeric SHG intensity pattern of skeletal muscles. , 2011, Biophysical journal.

[12]  J. Zweier,et al.  Tetrahydrobiopterin depletion and NOS2 uncoupling contribute to heart failure-induced alterations in atrial electrophysiology. , 2011, Cardiovascular research.

[13]  S. Dikalov,et al.  EPR detection of cellular and mitochondrial superoxide using cyclic hydroxylamines , 2011, Free radical research.

[14]  G. Recher,et al.  Skeletal muscle sarcomeric SHG patterns photo-conversion by femtosecond infrared laser , 2011, Biomedical optics express.

[15]  G. Cohen,et al.  Signaling and cytotoxic functions of 4-hydroxyalkenals. , 2010, American journal of physiology. Endocrinology and metabolism.

[16]  Mayandi Sivaguru,et al.  Quantitative analysis of collagen fiber organization in injured tendons using Fourier transform-second harmonic generation imaging. , 2010, Optics express.

[17]  R. Kitsis,et al.  Cell death in the pathogenesis of heart disease: mechanisms and significance. , 2010, Annual review of physiology.

[18]  S. Luo,et al.  Protein carbonylation: avoiding pitfalls in the 2,4-dinitrophenylhydrazine assay , 2009, Redox report : communications in free radical research.

[19]  P. Wołkow,et al.  Enhanced oxidative stress in hypertrophic cardiomyopathy , 2009, Pharmacological reports : PR.

[20]  I. Efimov,et al.  Resolution of Established Cardiac Hypertrophy and Fibrosis and Prevention of Systolic Dysfunction in a Transgenic Rabbit Model of Human Cardiomyopathy Through Thiol-Sensitive Mechanisms , 2009, Circulation.

[21]  F. T. ten Cate,et al.  Cardiac Myosin-Binding Protein C Mutations and Hypertrophic Cardiomyopathy: Haploinsufficiency, Deranged Phosphorylation, and Cardiomyocyte Dysfunction , 2009, Circulation.

[22]  L. Wojnar,et al.  Detection of mitochondrial dysfunction by EPR technique in mouse model of dilated cardiomyopathy. , 2008, Free radical biology & medicine.

[23]  A. Marian,et al.  Differential interactions of thin filament proteins in two cardiac troponin T mouse models of hypertrophic and dilated cardiomyopathies. , 2008, Cardiovascular research.

[24]  William A Mohler,et al.  Measurement of muscle disease by quantitative second-harmonic generation imaging. , 2008, Journal of biomedical optics.

[25]  A. Marian,et al.  Antifibrotic effects of antioxidant N-acetylcysteine in a mouse model of human hypertrophic cardiomyopathy mutation. , 2006, Journal of the American College of Cardiology.

[26]  William A Mohler,et al.  Characterization of the myosin-based source for second-harmonic generation from muscle sarcomeres. , 2006, Biophysical journal.

[27]  D. Kass,et al.  Role of Cardiac Myosin Binding Protein C in Sustaining Left Ventricular Systolic Stiffening , 2004, Circulation research.

[28]  M. Duchen.  Roles of mitochondria in health and disease. , 2004, Diabetes.

[29]  Roberto Colombo,et al.  Protein carbonyl groups as biomarkers of oxidative stress. , 2003, Clinica chimica acta; international journal of clinical chemistry.

[30]  Elias S. J. Arnér,et al.  Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. , 2001, Free radical biology & medicine.

[31]  F. Foury,et al.  Mitochondrial Control of Iron Homeostasis , 2001, The Journal of Biological Chemistry.

[32]  F J Schoen,et al.  Comparison of Two Murine Models of Familial Hypertrophic Cardiomyopathy , 2001, Circulation research.

[33]  Ò. Miró,et al.  Mitochondrial function in heart muscle from patients with idiopathic dilated cardiomyopathy. , 2000, Cardiovascular research.

[34]  A. Takeshita,et al.  Direct evidence for increased hydroxyl radicals originating from superoxide in the failing myocardium. , 2000, Circulation research.

[35]  D. Betteridge,et al.  What is oxidative stress? , 2000, Metabolism: clinical and experimental.

[36]  D. Kass,et al.  Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice. , 1999, The Journal of clinical investigation.

[37]  A. Takeshita,et al.  Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. , 1999, Circulation research.

[38]  L. Placer,et al.  Cardiomyopathies and oxidative stress. , 1996, Medical hypotheses.

[39]  B. Halliwell.  Oxidative stress, nutrition and health. Experimental strategies for optimization of nutritional antioxidant intake in humans. , 1996, Free radical research.

[40]  M. Burch,et al.  Hypertrophic cardiomyopathy. , 1994, Archives of disease in childhood.

[41]  B. Halliwell,et al.  Lipid peroxidation: its mechanism, measurement, and significance. , 1993, The American journal of clinical nutrition.

[42]  D. Butterfield,et al.  Measurement of oxidized/reduced glutathione ratio. , 2010, Methods in molecular biology.

[43]  S. Morimoto.  Sarcomeric proteins and inherited cardiomyopathies. , 2008, Cardiovascular research.

[44]  R. Gottlieb,et al.  Heart mitochondria: gates of life and death. , 2008, Cardiovascular research.

[45]  J. Pincemail,et al.  [Oxidative stress]. , 2007, Revue medicale de Liege.

[46]  Hiroyuki Tsutsui,et al.  [Oxidative stress and heart failure]. , 2006, Nihon rinsho. Japanese journal of clinical medicine.

[47]  H. Canatan,et al.  Increased oxidative stress in dilated cardiomyopathic heart failure. , 1998, Clinical chemistry.

[48]  G. Poli,et al.  Oxidative damage and fibrogenesis. , 1997, Free radical biology & medicine.

[49]  H. Esterbauer,et al.  Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. , 1991, Free radical biology & medicine.