Funded in part by Boehringer Ingelheim Fonds
Decreased creatine kinase is linked to diastolic dysfunction in rats with right heart failure induced by pulmonary artery hypertension
Fowler ED, Benoist D, Drinkhill MJ, Stones R, Helmes M, Wüst RC, Stienen GJ, Steele DS, White E
Journal of molecular and cellular cardiology · 45 citations
Review labels
Neutral facts our review recorded about how this study was done. They describe method, never whether we like the result.
How it was studied
- Design
- Animal study (classified by our AI screen)
- Studied in
- Animals
- Main outcome
- Health markers and function
Who paid for it
- Funding
- Industry funded
- Nonprofit
- British Heart Foundation
- University or hospital
- University of Leeds
- Company
- Boehringer Ingelheim Fonds
- Authors
- At least one author declares a financial tie to industry
- Grants
- British Heart Foundation (RG/11/10/28924); British Heart Foundation (PG/13/3/29924)
Based on 3 listed funder(s) and full-text disclosure statement.
Publication
- Published
- 2015-06-24 · J Mol Cell Cardiol · vol. 86 · pp. 1–8
- Publisher
- Elsevier BV
- Cited
- 49 citations · more than 91% of similar papers · 2.6× the field average
- Impact
- Top 10% most cited in its field
- References
- 47 works
- Access
- Open access (hybrid journal) · CC-BY
- Research areas
- Cardiovascular Effects of Exercise · Pulmonary Hypertension Research and Treatments · Cardiomyopathy and Myosin Studies
- Keywords
- Internal medicine, Sarcomere, Creatine kinase, Cardiology, Diastole, Heart failure, Pulmonary artery, Medicine, Myocyte, Ventricle, Pulmonary hypertension, Creatine, Endocrinology, Blood pressure
- MeSH
- sarcomeres, myocardium, pulmonary artery, myocytes, cardiac, animals, humans, rats, hypertension, pulmonary, ventricular dysfunction, right, calcium, creatine kinase, adenosine triphosphate, diastole, heart failure
9 authors
From GB, FR, US, NL
- Ewan Douglas FowlerUniversity of Leeds
- David BenoîstUniversity of Leeds; Université de Bordeaux; Inserm; Electrophysiology and Heart Modeling Institute; Centre de Recherche Cardio-Thoracique de Bordeaux
- Mark J. DrinkhillUniversity of Leeds
- Rachel StonesUniversity of Leeds
- Michiel HelmesIntralytix (United States); Amsterdam Cardiovascular Sciences; Amsterdam UMC Location Vrije Universiteit Amsterdam
- Rob C. I. WüstAmsterdam Cardiovascular Sciences; Amsterdam UMC Location Vrije Universiteit Amsterdam
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.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY).
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