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Cardiovascular Research Advance Access originally published online on April 14, 2008
Cardiovascular Research 2008 79(3):481-491; doi:10.1093/cvr/cvn094
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

The molecular phenotype of human cardiac myosin associated with hypertrophic obstructive cardiomyopathy

Adam M. Jacques1, Natalia Briceno1, Andrew E. Messer1, Clare E. Gallon1, Shapour Jalilzadeh2, Edwin Garcia1, Gaelle Kikonda-Kanda1, Jennifer Goddard2, Sian E. Harding1, Hugh Watkins2, M. Tomé Esteban3, Victor T. Tsang3, William J. McKenna3 and Steven B. Marston1,*

1 Cardiac Medicine, National Heart and Lung Institute, Imperial College London, Guy Scadding Building, Dovehouse Street, London, UK
2 Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford, UK
3 Institute of Cardiovascular Science, University College London, London, UK

* Corresponding author. Tel: +44 20 7351 8147; fax: +44 20 7823 3392.E-mail address: s.marston{at}imperial.ac.uk

Aim: The aim of the study was to compare the functional and structural properties of the motor protein, myosin, and isolated myocyte contractility in heart muscle excised from hypertrophic cardiomyopathy patients by surgical myectomy with explanted failing heart and non-failing donor heart muscle.

Methods: Myosin was isolated and studied using an in vitro motility assay. The distribution of myosin light chain-1 isoforms was measured by two-dimensional electrophoresis. Myosin light chain-2 phosphorylation was measured by sodium dodecyl sulphate–polyacrylamide gel electrophoresis using Pro-Q Diamond phosphoprotein stain.

Results: The fraction of actin filaments moving when powered by myectomy myosin was 21% less than with donor myosin (P = 0.006), whereas the sliding speed was not different (0.310 ± 0.034 for myectomy myosin vs. 0.305 ± 0.019 µm/s for donor myosin in six paired experiments). Failing heart myosin showed 18% reduced motility. One myectomy myosin sample produced a consistently higher sliding speed than donor heart myosin and was identified with a disease-causing heavy chain mutation (V606M). In myectomy myosin, the level of atrial light chain-1 relative to ventricular light chain-1 was 20 ± 5% compared with 11 ± 5% in donor heart myosin and the level of myosin light chain-2 phosphorylation was decreased by 30–45%. Isolated cardiomyocytes showed reduced contraction amplitude (1.61 ± 0.25 vs. 3.58 ± 0.40%) and reduced relaxation rates compared with donor myocytes (TT50% = 0.32 ± 0.09 vs. 0.17 ± 0.02 s).

Conclusion: Contractility in myectomy samples resembles the hypocontractile phenotype found in end-stage failing heart muscle irrespective of the primary stimulus, and this phenotype is not a direct effect of the hypertrophy-inducing mutation. The presence of a myosin heavy chain mutation causing hypertrophic cardiomyopathy can be predicted from a simple functional assay.

KEYWORDS Contractile apparatus; Contractile function; Hypertrophy; Protein phosphorylation; Myosin; Myectomy; Hypertrophic cardiomyopathy

Time for primary review: 37 days


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