Format

Send to

Choose Destination
J Mol Cell Cardiol. 2015 Sep;86:1-8. doi: 10.1016/j.yjmcc.2015.06.016. Epub 2015 Jun 24.

Decreased creatine kinase is linked to diastolic dysfunction in rats with right heart failure induced by pulmonary artery hypertension.

Author information

1
Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK.
2
Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK; L'Institut de Rythmologie et Modélisation Cardiaque, Inserm U-1045, Université de Bordeaux, France.
3
Department of Physiology, Institute for Cardiovascular Research, VU University Medical Centre, Amsterdam, The Netherlands; IonOptix LLC, Milton, MA, USA.
4
Department of Physiology, Institute for Cardiovascular Research, VU University Medical Centre, Amsterdam, The Netherlands.
5
Department of Physiology, Institute for Cardiovascular Research, VU University Medical Centre, Amsterdam, The Netherlands; Department of Physics and Astronomy, Faculty of Science, VU University, Amsterdam, The Netherlands.
6
Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK. Electronic address: e.white@leeds.ac.uk.

Abstract

Our objective was to investigate the role of creatine kinase in the contractile dysfunction of right ventricular failure caused by pulmonary artery hypertension. Pulmonary artery hypertension and right ventricular failure were induced in rats by monocrotaline and compared to saline-injected control animals. In vivo right ventricular diastolic pressure-volume relationships were measured in anesthetized animals; diastolic force-length relationships in single enzymatically dissociated myocytes and myocardial creatine kinase levels by Western blot. We observed diastolic dysfunction in right ventricular failure indicated by significantly steeper diastolic pressure-volume relationships in vivo and diastolic force-length relationships in single myocytes. There was a significant reduction in creatine kinase protein expression in failing right ventricle. Dysfunction also manifested as a shorter diastolic sarcomere length in failing myocytes. This was associated with a Ca(2+)-independent mechanism that was sensitive to cross-bridge cycling inhibition. In saponin-skinned failing myocytes, addition of exogenous creatine kinase significantly lengthened sarcomeres, while in intact healthy myocytes, inhibition of creatine kinase significantly shortened sarcomeres. Creatine kinase inhibition also changed the relatively flat contraction amplitude-stimulation frequency relationship of healthy myocytes into a steeply negative, failing phenotype. Decreased creatine kinase expression leads to diastolic dysfunction. We propose that this is via local reduction in ATP:ADP ratio and thus to Ca(2+)-independent force production and diastolic sarcomere shortening. Creatine kinase inhibition also mimics a definitive characteristic of heart failure, the inability to respond to increased demand. Novel therapies for pulmonary artery hypertension are needed. Our data suggest that cardiac energetics would be a potential ventricular therapeutic target.

KEYWORDS:

Creatine kinase; Diastolic sarcomere length; Monocrotaline; Pulmonary artery hypertension; Right ventricular failure

PMID:
26116865
PMCID:
PMC4564291
DOI:
10.1016/j.yjmcc.2015.06.016
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center