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Active Inhibitor-1 Maintains Protein Hyper-Phosphorylation in Aging Hearts and Halts Remodeling in Failing Hearts

Impaired sarcoplasmic reticulum calcium cycling and depressed contractility are key characteristics in heart failure. Defects in sarcoplasmic reticulum function are characterized by decreased SERCA2a Ca-transport that is partially attributable to dephosphorylation of its regulator phospholamban by i...

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Autores principales: Pritchard, Tracy J., Kawase, Yoshiaki, Haghighi, Kobra, Anjak, Ahmad, Cai, Wenfeng, Jiang, Min, Nicolaou, Persoulla, Pylar, George, Karakikes, Ioannis, Rapti, Kleopatra, Rubinstein, Jack, Hajjar, Roger J., Kranias, Evangelia G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3846572/
https://www.ncbi.nlm.nih.gov/pubmed/24312496
http://dx.doi.org/10.1371/journal.pone.0080717
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author Pritchard, Tracy J.
Kawase, Yoshiaki
Haghighi, Kobra
Anjak, Ahmad
Cai, Wenfeng
Jiang, Min
Nicolaou, Persoulla
Pylar, George
Karakikes, Ioannis
Rapti, Kleopatra
Rubinstein, Jack
Hajjar, Roger J.
Kranias, Evangelia G.
author_facet Pritchard, Tracy J.
Kawase, Yoshiaki
Haghighi, Kobra
Anjak, Ahmad
Cai, Wenfeng
Jiang, Min
Nicolaou, Persoulla
Pylar, George
Karakikes, Ioannis
Rapti, Kleopatra
Rubinstein, Jack
Hajjar, Roger J.
Kranias, Evangelia G.
author_sort Pritchard, Tracy J.
collection PubMed
description Impaired sarcoplasmic reticulum calcium cycling and depressed contractility are key characteristics in heart failure. Defects in sarcoplasmic reticulum function are characterized by decreased SERCA2a Ca-transport that is partially attributable to dephosphorylation of its regulator phospholamban by increased protein phosphatase 1 activity. Inhibition of protein phosphatase 1 through activation of its endogenous inhibitor-1 has been shown to enhance cardiac Ca-handling and contractility as well as protect from pathological stress remodeling in young mice. In this study, we assessed the long-term effects of inducible expression of constitutively active inhibitor-1 in the adult heart and followed function and remodeling through the aging process, up to 20 months. Mice with inhibitor-1 had normal survival and similar function to WTs. There was no overt remodeling as evidenced by measures of left ventricular end-systolic and diastolic diameters and posterior wall dimensions, heart weight to tibia length ratio, and histology. Higher phosphorylation of phospholamban at both Ser16 and Thr17 was maintained in aged hearts with active inhibitor-1, potentially offsetting the effects of elevated Ser2815-phosphorylation in ryanodine receptor, as there were no increases in arrhythmias under stress conditions in 20-month old mice. Furthermore, long-term expression of active inhibitor-1 via recombinant adeno-associated virus type 9 gene transfer in rats with pressure-overload induced heart failure improved function and prevented remodeling, associated with increased phosphorylation of phospholamban at Ser16 and Thr17. Thus, chronic inhibition of protein phosphatase 1, through increases in active inhibitor-1, does not accelerate age-related cardiomyopathy and gene transfer of this molecule in vivo improves function and halts remodeling in the long term.
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spelling pubmed-38465722013-12-05 Active Inhibitor-1 Maintains Protein Hyper-Phosphorylation in Aging Hearts and Halts Remodeling in Failing Hearts Pritchard, Tracy J. Kawase, Yoshiaki Haghighi, Kobra Anjak, Ahmad Cai, Wenfeng Jiang, Min Nicolaou, Persoulla Pylar, George Karakikes, Ioannis Rapti, Kleopatra Rubinstein, Jack Hajjar, Roger J. Kranias, Evangelia G. PLoS One Research Article Impaired sarcoplasmic reticulum calcium cycling and depressed contractility are key characteristics in heart failure. Defects in sarcoplasmic reticulum function are characterized by decreased SERCA2a Ca-transport that is partially attributable to dephosphorylation of its regulator phospholamban by increased protein phosphatase 1 activity. Inhibition of protein phosphatase 1 through activation of its endogenous inhibitor-1 has been shown to enhance cardiac Ca-handling and contractility as well as protect from pathological stress remodeling in young mice. In this study, we assessed the long-term effects of inducible expression of constitutively active inhibitor-1 in the adult heart and followed function and remodeling through the aging process, up to 20 months. Mice with inhibitor-1 had normal survival and similar function to WTs. There was no overt remodeling as evidenced by measures of left ventricular end-systolic and diastolic diameters and posterior wall dimensions, heart weight to tibia length ratio, and histology. Higher phosphorylation of phospholamban at both Ser16 and Thr17 was maintained in aged hearts with active inhibitor-1, potentially offsetting the effects of elevated Ser2815-phosphorylation in ryanodine receptor, as there were no increases in arrhythmias under stress conditions in 20-month old mice. Furthermore, long-term expression of active inhibitor-1 via recombinant adeno-associated virus type 9 gene transfer in rats with pressure-overload induced heart failure improved function and prevented remodeling, associated with increased phosphorylation of phospholamban at Ser16 and Thr17. Thus, chronic inhibition of protein phosphatase 1, through increases in active inhibitor-1, does not accelerate age-related cardiomyopathy and gene transfer of this molecule in vivo improves function and halts remodeling in the long term. Public Library of Science 2013-12-02 /pmc/articles/PMC3846572/ /pubmed/24312496 http://dx.doi.org/10.1371/journal.pone.0080717 Text en © 2013 Pritchard et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Pritchard, Tracy J.
Kawase, Yoshiaki
Haghighi, Kobra
Anjak, Ahmad
Cai, Wenfeng
Jiang, Min
Nicolaou, Persoulla
Pylar, George
Karakikes, Ioannis
Rapti, Kleopatra
Rubinstein, Jack
Hajjar, Roger J.
Kranias, Evangelia G.
Active Inhibitor-1 Maintains Protein Hyper-Phosphorylation in Aging Hearts and Halts Remodeling in Failing Hearts
title Active Inhibitor-1 Maintains Protein Hyper-Phosphorylation in Aging Hearts and Halts Remodeling in Failing Hearts
title_full Active Inhibitor-1 Maintains Protein Hyper-Phosphorylation in Aging Hearts and Halts Remodeling in Failing Hearts
title_fullStr Active Inhibitor-1 Maintains Protein Hyper-Phosphorylation in Aging Hearts and Halts Remodeling in Failing Hearts
title_full_unstemmed Active Inhibitor-1 Maintains Protein Hyper-Phosphorylation in Aging Hearts and Halts Remodeling in Failing Hearts
title_short Active Inhibitor-1 Maintains Protein Hyper-Phosphorylation in Aging Hearts and Halts Remodeling in Failing Hearts
title_sort active inhibitor-1 maintains protein hyper-phosphorylation in aging hearts and halts remodeling in failing hearts
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3846572/
https://www.ncbi.nlm.nih.gov/pubmed/24312496
http://dx.doi.org/10.1371/journal.pone.0080717
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