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Phosphodiesterase 5 inhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in heart failure

Heart failure (HF) is characterized by poor survival, a loss of catecholamine reserve and cellular structural remodeling in the form of disorganization and loss of the transverse tubule network. Indeed, survival rates for HF are worse than many common cancers and have not improved over time. Tadalaf...

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Autores principales: Lawless, Michael, Caldwell, Jessica L., Radcliffe, Emma J., Smith, Charlotte E. R., Madders, George W. P., Hutchings, David C., Woods, Lori S., Church, Stephanie J., Unwin, Richard D., Kirkwood, Graeme J., Becker, Lorenz K., Pearman, Charles M., Taylor, Rebecca F., Eisner, David A., Dibb, Katharine M., Trafford, Andrew. W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494852/
https://www.ncbi.nlm.nih.gov/pubmed/31043634
http://dx.doi.org/10.1038/s41598-019-42592-1
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author Lawless, Michael
Caldwell, Jessica L.
Radcliffe, Emma J.
Smith, Charlotte E. R.
Madders, George W. P.
Hutchings, David C.
Woods, Lori S.
Church, Stephanie J.
Unwin, Richard D.
Kirkwood, Graeme J.
Becker, Lorenz K.
Pearman, Charles M.
Taylor, Rebecca F.
Eisner, David A.
Dibb, Katharine M.
Trafford, Andrew. W.
author_facet Lawless, Michael
Caldwell, Jessica L.
Radcliffe, Emma J.
Smith, Charlotte E. R.
Madders, George W. P.
Hutchings, David C.
Woods, Lori S.
Church, Stephanie J.
Unwin, Richard D.
Kirkwood, Graeme J.
Becker, Lorenz K.
Pearman, Charles M.
Taylor, Rebecca F.
Eisner, David A.
Dibb, Katharine M.
Trafford, Andrew. W.
author_sort Lawless, Michael
collection PubMed
description Heart failure (HF) is characterized by poor survival, a loss of catecholamine reserve and cellular structural remodeling in the form of disorganization and loss of the transverse tubule network. Indeed, survival rates for HF are worse than many common cancers and have not improved over time. Tadalafil is a clinically relevant drug that blocks phosphodiesterase 5 with high specificity and is used to treat erectile dysfunction. Using a sheep model of advanced HF, we show that tadalafil treatment improves contractile function, reverses transverse tubule loss, restores calcium transient amplitude and the heart’s response to catecholamines. Accompanying these effects, tadalafil treatment normalized BNP mRNA and prevented development of subjective signs of HF. These effects were independent of changes in myocardial cGMP content and were associated with upregulation of both monomeric and dimerized forms of protein kinase G and of the cGMP hydrolyzing phosphodiesterases 2 and 3. We propose that the molecular switch for the loss of transverse tubules in HF and their restoration following tadalafil treatment involves the BAR domain protein Amphiphysin II (BIN1) and the restoration of catecholamine sensitivity is through reductions in G-protein receptor kinase 2, protein phosphatase 1 and protein phosphatase 2 A abundance following phosphodiesterase 5 inhibition.
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spelling pubmed-64948522019-05-17 Phosphodiesterase 5 inhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in heart failure Lawless, Michael Caldwell, Jessica L. Radcliffe, Emma J. Smith, Charlotte E. R. Madders, George W. P. Hutchings, David C. Woods, Lori S. Church, Stephanie J. Unwin, Richard D. Kirkwood, Graeme J. Becker, Lorenz K. Pearman, Charles M. Taylor, Rebecca F. Eisner, David A. Dibb, Katharine M. Trafford, Andrew. W. Sci Rep Article Heart failure (HF) is characterized by poor survival, a loss of catecholamine reserve and cellular structural remodeling in the form of disorganization and loss of the transverse tubule network. Indeed, survival rates for HF are worse than many common cancers and have not improved over time. Tadalafil is a clinically relevant drug that blocks phosphodiesterase 5 with high specificity and is used to treat erectile dysfunction. Using a sheep model of advanced HF, we show that tadalafil treatment improves contractile function, reverses transverse tubule loss, restores calcium transient amplitude and the heart’s response to catecholamines. Accompanying these effects, tadalafil treatment normalized BNP mRNA and prevented development of subjective signs of HF. These effects were independent of changes in myocardial cGMP content and were associated with upregulation of both monomeric and dimerized forms of protein kinase G and of the cGMP hydrolyzing phosphodiesterases 2 and 3. We propose that the molecular switch for the loss of transverse tubules in HF and their restoration following tadalafil treatment involves the BAR domain protein Amphiphysin II (BIN1) and the restoration of catecholamine sensitivity is through reductions in G-protein receptor kinase 2, protein phosphatase 1 and protein phosphatase 2 A abundance following phosphodiesterase 5 inhibition. Nature Publishing Group UK 2019-05-01 /pmc/articles/PMC6494852/ /pubmed/31043634 http://dx.doi.org/10.1038/s41598-019-42592-1 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Lawless, Michael
Caldwell, Jessica L.
Radcliffe, Emma J.
Smith, Charlotte E. R.
Madders, George W. P.
Hutchings, David C.
Woods, Lori S.
Church, Stephanie J.
Unwin, Richard D.
Kirkwood, Graeme J.
Becker, Lorenz K.
Pearman, Charles M.
Taylor, Rebecca F.
Eisner, David A.
Dibb, Katharine M.
Trafford, Andrew. W.
Phosphodiesterase 5 inhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in heart failure
title Phosphodiesterase 5 inhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in heart failure
title_full Phosphodiesterase 5 inhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in heart failure
title_fullStr Phosphodiesterase 5 inhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in heart failure
title_full_unstemmed Phosphodiesterase 5 inhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in heart failure
title_short Phosphodiesterase 5 inhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in heart failure
title_sort phosphodiesterase 5 inhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in heart failure
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494852/
https://www.ncbi.nlm.nih.gov/pubmed/31043634
http://dx.doi.org/10.1038/s41598-019-42592-1
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