title: N-acetylcysteine reverses diastolic dysfunction and hypertrophy in familial hypertrophic cardiomyopathy.
abstract: S-glutathionylation of cardiac myosin-binding protein C (cMyBP-C) induces Ca(2+) sensitization and a slowing of cross-bridge kinetics as a result of increased oxidative signaling. Although there is evidence for a role of oxidative stress in disorders associated with hypertrophic cardiomyopathy (HCM), this mechanism is not well understood. We investigated whether oxidative myofilament modifications may be in part responsible for diastolic dysfunction in HCM. We administered N-acetylcysteine (NAC) for 30 days to 1-mo-old wild-type mice and to transgenic mice expressing a mutant tropomyosin (Tm-E180G) and nontransgenic littermates. Tm-E180G hearts demonstrate a phenotype similar to human HCM. After NAC administration, the morphology and diastolic function of Tm-E180G mice was not significantly different from controls, indicating that NAC had reversed baseline diastolic dysfunction and hypertrophy in our model. NAC administration also increased sarco(endo)plasmic reticulum Ca(2+) ATPase protein expression, reduced extracellular signal-related kinase 1/2 phosphorylation, and normalized phosphorylation of phospholamban, as assessed by Western blot. Detergent-extracted fiber bundles from NAC-administered Tm-E180G mice showed nearly nontransgenic (NTG) myofilament Ca(2+) sensitivity. Additionally, we found that NAC increased tension cost and rate of cross-bridge reattachment. Tm-E180G myofilaments were found to have a significant increase in S-glutathionylation of cMyBP-C, which was returned to NTG levels upon NAC administration. Taken together, our results indicate that oxidative myofilament modifications are an important mediator in diastolic function, and by relieving this modification we were able to reverse established diastolic dysfunction and hypertrophy in HCM.
authors.affiliation: Department of Physiology and Biophysics and the Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, Chicago, Illinois; Department of Biology, College of Science and Technology, Florida A & M University, Tallahassee, Florida;
authors.forename: Tanganyika
authors.initials: T
authors.lastname: Wilder
authors.affiliation: Department of Physiology and Biophysics and the Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, Chicago, Illinois;
authors.forename: David M
authors.initials: DM
authors.lastname: Ryba
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: David F
authors.initials: DF
authors.lastname: Wieczorek
authors.affiliation: Department of Physiology and Biophysics and the Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, Chicago, Illinois; Department of Medicine, Section of Cardiology, University of Illinois at Chicago, Chicago, Illinois; and.
authors.forename: Beata M
authors.initials: BM
authors.lastname: Wolska
authors.affiliation: Department of Physiology and Biophysics and the Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, Chicago, Illinois; solarorj@uic.edu.
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D003971:Diastole / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D009210:Myofibrils / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000187:drug effects / Q000378:metabolism; D014335:Tropomyosin / Q000235:genetics; D000099211:Phospholamban; D000099163:Myosin Binding Protein C
chemical_list: D000111:Acetylcysteine; D002118:Calcium; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D016166:Free Radical Scavengers; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D014335:Tropomyosin; D000099211:Phospholamban; D000099163:Myosin Binding Protein C
keywords: S-glutathionylation; cardiac myosin-binding protein C; diastolic dysfunction; oxidative stress; sarcomeres