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Conserved expression and functions of PDE4 in rodent and human heart

PDE4 isoenzymes are critical in the control of cAMP signaling in rodent cardiac myocytes. Ablation of PDE4 affects multiple key players in excitation–contraction coupling and predisposes mice to the development of heart failure. As little is known about PDE4 in human heart, we explored to what exten...

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Autores principales: Richter, Wito, Xie, Moses, Scheitrum, Colleen, Krall, Judith, Movsesian, Matthew A., Conti, Marco
Formato: Texto
Lenguaje:English
Publicado: Springer-Verlag 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032896/
https://www.ncbi.nlm.nih.gov/pubmed/21161247
http://dx.doi.org/10.1007/s00395-010-0138-8
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author Richter, Wito
Xie, Moses
Scheitrum, Colleen
Krall, Judith
Movsesian, Matthew A.
Conti, Marco
author_facet Richter, Wito
Xie, Moses
Scheitrum, Colleen
Krall, Judith
Movsesian, Matthew A.
Conti, Marco
author_sort Richter, Wito
collection PubMed
description PDE4 isoenzymes are critical in the control of cAMP signaling in rodent cardiac myocytes. Ablation of PDE4 affects multiple key players in excitation–contraction coupling and predisposes mice to the development of heart failure. As little is known about PDE4 in human heart, we explored to what extent cardiac expression and functions of PDE4 are conserved between rodents and humans. We find considerable similarities including comparable amounts of PDE4 activity expressed, expression of the same PDE4 subtypes and splicing variants, anchoring of PDE4 to the same subcellular compartments and macromolecular signaling complexes, and downregulation of PDE4 activity and protein in heart failure. The major difference between the species is a fivefold higher amount of non-PDE4 activity in human hearts compared to rodents. As a consequence, the effect of PDE4 inactivation is different in rodents and humans. PDE4 inhibition leads to increased phosphorylation of virtually all PKA substrates in mouse cardiomyocytes, but increased phosphorylation of only a restricted number of proteins in human cardiomyocytes. Our findings suggest that PDE4s have a similar role in the local regulation of cAMP signaling in rodent and human heart. However, inhibition of PDE4 has ‘global’ effects on cAMP signaling only in rodent hearts, as PDE4 comprises a large fraction of the total cardiac PDE activity in rodents but not in humans. These differences may explain the distinct pharmacological effects of PDE4 inhibition in rodent and human hearts. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00395-010-0138-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-30328962011-03-16 Conserved expression and functions of PDE4 in rodent and human heart Richter, Wito Xie, Moses Scheitrum, Colleen Krall, Judith Movsesian, Matthew A. Conti, Marco Basic Res Cardiol Original Contribution PDE4 isoenzymes are critical in the control of cAMP signaling in rodent cardiac myocytes. Ablation of PDE4 affects multiple key players in excitation–contraction coupling and predisposes mice to the development of heart failure. As little is known about PDE4 in human heart, we explored to what extent cardiac expression and functions of PDE4 are conserved between rodents and humans. We find considerable similarities including comparable amounts of PDE4 activity expressed, expression of the same PDE4 subtypes and splicing variants, anchoring of PDE4 to the same subcellular compartments and macromolecular signaling complexes, and downregulation of PDE4 activity and protein in heart failure. The major difference between the species is a fivefold higher amount of non-PDE4 activity in human hearts compared to rodents. As a consequence, the effect of PDE4 inactivation is different in rodents and humans. PDE4 inhibition leads to increased phosphorylation of virtually all PKA substrates in mouse cardiomyocytes, but increased phosphorylation of only a restricted number of proteins in human cardiomyocytes. Our findings suggest that PDE4s have a similar role in the local regulation of cAMP signaling in rodent and human heart. However, inhibition of PDE4 has ‘global’ effects on cAMP signaling only in rodent hearts, as PDE4 comprises a large fraction of the total cardiac PDE activity in rodents but not in humans. These differences may explain the distinct pharmacological effects of PDE4 inhibition in rodent and human hearts. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00395-010-0138-8) contains supplementary material, which is available to authorized users. Springer-Verlag 2010-12-16 2011 /pmc/articles/PMC3032896/ /pubmed/21161247 http://dx.doi.org/10.1007/s00395-010-0138-8 Text en © The Author(s) 2010 https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Original Contribution
Richter, Wito
Xie, Moses
Scheitrum, Colleen
Krall, Judith
Movsesian, Matthew A.
Conti, Marco
Conserved expression and functions of PDE4 in rodent and human heart
title Conserved expression and functions of PDE4 in rodent and human heart
title_full Conserved expression and functions of PDE4 in rodent and human heart
title_fullStr Conserved expression and functions of PDE4 in rodent and human heart
title_full_unstemmed Conserved expression and functions of PDE4 in rodent and human heart
title_short Conserved expression and functions of PDE4 in rodent and human heart
title_sort conserved expression and functions of pde4 in rodent and human heart
topic Original Contribution
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032896/
https://www.ncbi.nlm.nih.gov/pubmed/21161247
http://dx.doi.org/10.1007/s00395-010-0138-8
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