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      N-acetylcysteine reverses diastolic dysfunction and hypertrophy in familial hypertrophic cardiomyopathy

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          Abstract

          Novel findings include reversal of established hypertrophy, left atrial dilation, and diastolic dysfunction in a model of HCM treated with the antioxidant N-acetylcysteine. This was associated with a reduction in S-glutathionylation of myofilament proteins, which was increased in untreated controls, a decrease in myofilament Ca 2+ response, and hastening of cross-bridge kinetics.

          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.

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          Author and article information

          Journal
          Am J Physiol Heart Circ Physiol
          Am. J. Physiol. Heart Circ. Physiol
          ajpheart
          ajpheart
          AJPHEART
          American Journal of Physiology - Heart and Circulatory Physiology
          American Physiological Society (Bethesda, MD )
          0363-6135
          1522-1539
          2 October 2015
          15 November 2015
          15 November 2016
          : 309
          : 10
          : H1720-H1730
          Affiliations
          [1] 1Department of Physiology and Biophysics and the Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, Chicago, Illinois;
          [2] 2Department of Biology, College of Science and Technology, Florida A & M University, Tallahassee, Florida;
          [3] 3Department of Medicine, Section of Cardiology, University of Illinois at Chicago, Chicago, Illinois; and
          [4] 4Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio
          Author notes
          [*]

          T. Wilder and D. M. Ryba contributed equally to this work.

          Address for reprint requests and other correspondence: R. J. Solaro, Dept. of Physiology and Biophysics (M/C 901), College of Medicine, 835 S. Wolcott Ave., Univ. of Illinois at Chicago, Chicago, IL 60612 (e-mail: solarorj@ 123456uic.edu ).
          Article
          PMC4666985 PMC4666985 4666985 H-00339-2015
          10.1152/ajpheart.00339.2015
          4666985
          26432840
          1ebb4a76-b292-4aff-b8ea-11766aee02aa
          Copyright © 2015 the American Physiological Society
          History
          : 11 May 2015
          : 25 September 2015
          Categories
          Muscle Mechanics and Ventricular Function

          sarcomeres,cardiac myosin-binding protein C,oxidative stress,diastolic dysfunction, S-glutathionylation

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