title: Decreased creatine kinase is linked to diastolic dysfunction in rats with right heart failure induced by pulmonary artery hypertension.
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.
authors.affiliation: Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK.
authors.forename: Ewan D
authors.initials: ED
authors.lastname: Fowler
authors.affiliation: Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK; L'Institut de Rythmologie et Modélisation Cardiaque, Inserm U-1045, Université de Bordeaux, France.
authors.forename: David
authors.initials: D
authors.lastname: Benoist
authors.affiliation: Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Drinkhill
authors.affiliation: Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Stones
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Centre, Amsterdam, The Netherlands; IonOptix LLC, Milton, MA, USA.
authors.forename: Michiel
authors.initials: M
authors.lastname: Helmes
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Rob C I
authors.initials: RC
authors.lastname: Wüst
authors.affiliation: 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.
authors.forename: Ger J M
authors.initials: GJ
authors.lastname: Stienen
authors.affiliation: Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK.
authors.forename: Derek S
authors.initials: DS
authors.lastname: Steele
authors.affiliation: Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK. Electronic address: e.white@leeds.ac.uk.
authors.forename: Ed
authors.initials: E
authors.lastname: White
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003402:Creatine Kinase / Q000096:biosynthesis / Q000378:metabolism*; D003971:Diastole; D006333:Heart Failure / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology* / Q000473:pathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D011651:Pulmonary Artery / Q000201:enzymology / Q000473:pathology; D051381:Rats; D012518:Sarcomeres / Q000201:enzymology / Q000473:pathology; D018497:Ventricular Dysfunction, Right / Q000201:enzymology* / Q000473:pathology
chemical_list: D000255:Adenosine Triphosphate; D003402:Creatine Kinase; D002118:Calcium
keywords: Creatine kinase; Diastolic sarcomere length; Monocrotaline; Pulmonary artery hypertension; Right ventricular failure