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 no...

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Published in:Oxidative medicine and cellular longevity 2015-01, Vol.2015 (2015), p.1-14
Main Authors: Sadayappan, Sakthivel, van der Velden, Jolanda, Govindan, Suresh, Barefield, David, Michels, Michelle, Cardounel, Arturo J., Velayutham, Murugesan, Sivaguru, Mayandi, Lynch, Thomas L., Remedios, Cristobal dos
Format: Article
Language:English
Subjects:
Adolescent
Adult
Anatomy & physiology
Animals
Antioxidants
Cardiomyopathy
Cardiomyopathy, Dilated
Cardiomyopathy, Dilated - genetics
Cardiomyopathy, Dilated - pathology
Carrier Proteins - genetics
Disease Models, Animal
Echocardiography
Electron Spin Resonance Spectroscopy
Female
Genetic aspects
Glutathione - metabolism
Heart
Heart - physiopathology
Homeostasis
Humans
Laboratory animals
Male
Malondialdehyde - metabolism
Mice
Middle Aged
Mitochondria
Mortality
Muscle proteins
Mutation
Myocardium - metabolism
Myosin
Oxidative Stress
Patients
Physiology
Protein binding
Protein Carbonylation
Proteins
Respiration
Rodents
Studies
Young Adult
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Summary: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.
ISSN:1942-0900
1942-0994
DOI:10.1155/2015/424751