Fowler, ED, Hauton, D, Boyle, J et al. (3 more authors) (2019) Energy Metabolism in the Failing Right Ventricle: Limitations of Oxygen Delivery and the Creatine Kinase System. International Journal of Molecular Sciences, 20 (8). 1805. ISSN 1661-6596
Abstract
Pulmonary arterial hypertension (PAH) results in hypertrophic remodeling of the right ventricle (RV) to overcome increased pulmonary pressure. This increases the O₂ consumption of the myocardium, and without a concomitant increase in energy generation, a mismatch with demand may occur. Eventually, RV function can no longer be sustained, and RV failure occurs. Beta-adrenergic blockers (BB) are thought to improve survival in left heart failure, in part by reducing energy expenditure and hypertrophy, however they are not currently a therapy for PAH. The monocrotaline (MCT) rat model of PAH was used to investigate the consequence of RV failure on myocardial oxygenation and mitochondrial function. A second group of MCT rats was treated daily with the beta-1 blocker metoprolol (MCT + BB). Histology confirmed reduced capillary density and increased capillary supply area without indications of capillary rarefaction in MCT rats. A computer model of O₂ flux was applied to the experimentally recorded capillary locations and predicted a reduction in mean tissue Po₂ in MCT rats. The fraction of hypoxic tissue (defined as Po₂ < 0.5 mmHg) was reduced following beta-1 blocker (BB) treatment. The functionality of the creatine kinase (CK) energy shuttle was measured in permeabilized RV myocytes by sequential ADP titrations in the presence and absence of creatine. Creatine significantly decreased the KmADP in cells from saline-injected control (CON) rats, but not MCT rats. The difference in KmADP with or without creatine was not different in MCT + BB cells compared to CON or MCT cells. Improved myocardial energetics could contribute to improved survival of PAH with chronic BB treatment.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
Keywords: | myocardial hypoxia; creatine kinase; pulmonary artery hypertension; beta blocker; monocrotaline; right ventricle failure; heart failure |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Funding Information: | Funder Grant number British Heart Foundation PG/13/3/29924 |
Depositing User: | Symplectic Publications |
Date Deposited: | 25 Apr 2019 09:02 |
Last Modified: | 25 Jun 2023 21:47 |
Status: | Published |
Publisher: | MDPI |
Identification Number: | 10.3390/ijms20081805 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:145020 |