期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 86, 期 -, 页码 1-8出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2015.06.016
关键词
Right ventricular failure; Creatine kinase; Diastolic sarcomere length; Pulmonary artery hypertension; Monocrotaline
资金
- University of Leeds PhD scholarship
- Emma and Leslie Reid PhD scholarship
- British Heart Foundation [PG/13/3/29924]
- CVON grant [2011-11-ARENA]
- Physiological Society
- Boehringer Ingelheim Fonds
- British Heart Foundation [RG/11/10/28924, PG/13/3/29924] Funding Source: researchfish
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 light 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 Ca2+-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 Ca2+-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. (C) 2015 The Authors. Published by Elsevier Ltd.
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