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

Fowler, Ewan D., Benoist, David, Drinkhill, Mark J., Stones, Rachel, Helmes, Michiel, Wüst, Rob C.I., Stienen, Ger J.M., Steele, Derek S. and White, Ed 2015. Decreased creatine kinase is linked to diastolic dysfunction in rats with right heart failure induced by pulmonary artery hypertension. Journal of Molecular and Cellular Cardiology 86 , pp. 1-8. 10.1016/j.yjmcc.2015.06.016

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Abstract

nd 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 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Biosciences
Publisher:	Elsevier
ISSN:	0022-2828
Date of First Compliant Deposit:	2 November 2021
Date of Acceptance:	22 June 2015
Last Modified:	17 Jun 2023 06:28
URI:	https://orca.cardiff.ac.uk/id/eprint/144672

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