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.
Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL 60153, USA.
Thomas L
TL
Lynch
Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Mayandi
M
Sivaguru
Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Murugesan
M
Velayutham
Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Arturo J
AJ
Cardounel
Department of Cardiology, Thoraxcenter, Erasmus Medical Center, 's-Gravendijkwal 230, 3015 CE Rotterdam, Netherlands.
Michelle
M
Michels
Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL 60153, USA.
David
D
Barefield
Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL 60153, USA.
Suresh
S
Govindan
Bosch Institute, Discipline of Anatomy and Histology, University of Sydney, Sydney, NSW 2006, Australia.
Cristobal
C
dos Remedios
Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, van der Boechorststraat 7, 1081 BT Amsterdam, Netherlands.
Jolanda
J
van der Velden
Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL 60153, USA.
Sakthivel
S
Sadayappan
D000293:Adolescent; D000328:Adult; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D004452:Echocardiography; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006321:Heart / Q000503:physiopathology; D006801:Humans; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D018384:Oxidative Stress; D050050:Protein Carbonylation; D055815:Young Adult; D000099163:Myosin Binding Protein C
D002352:Carrier Proteins; D005978:Glutathione; D008315:Malondialdehyde; D000099163:Myosin Binding Protein C