Constitutive glycogen synthase kinase-3α/β activity protects against chronic β-adrenergic remodelling of the heart

Ian G. Webb, Yasuhiro Nishino, James E. Clark, Colin Murdoch, Simon J. Walker, Marcus R. Makowski, Rene M. Botnar, Simon R. Redwood, Ajay M. Shah, Michael S. Marber

Research output: Contribution to journalArticle

Abstract

Aims

Glycogen synthase kinase 3 (GSK-3) signalling is implicated in the growth of the heart during development and in response to stress. However, its precise role remains unclear. We set out to characterize developmental growth and response to chronic isoproterenol (ISO) stress in knockin (KI) mice lacking the critical N-terminal serines, 21 of GSK-3α and 9 of GSK-3β respectively, required for inactivation by upstream kinases.
Methods and results

Between 5 and 15 weeks, KI mice grew more rapidly, but normalized heart weight and contractile performance were similar to wild-type (WT) mice. Isolated hearts of both genotypes responded comparably to acute ISO infusion with increases in heart rate and contractility. In WT mice, chronic subcutaneous ISO infusion over 14 days resulted in cardiac hypertrophy, interstitial fibrosis, and impaired contractility, accompanied by foetal gene reactivation. These effects were all significantly attenuated in KI mice. Indeed, ISO-treated KI hearts demonstrated reversible physiological remodelling traits with increased stroke volume and a preserved contractile response to acute adrenergic stimulation. Furthermore, simultaneous pharmacological inhibition of GSK-3 in KI mice treated with chronic subcutaneous ISO recapitulated the adverse remodelling phenotype seen in WT hearts.
Conclusion

Expression of inactivation-resistant GSK-3α/β does not affect eutrophic myocardial growth but protects against pathological hypertrophy induced by chronic adrenergic stimulation, maintaining cardiac function and attenuating interstitial fibrosis. Accordingly, strategies to prevent phosphorylation of Ser-21/9, and consequent inactivation of GSK-3α/β, may enable a sustained cardiac response to chronic β-agonist stimulation while preventing pathological remodelling.
LanguageEnglish
Pages494-503
Number of pages10
JournalCardiovascular Research
Volume87
Issue number3
Early online date17 Mar 2010
DOIs
Publication statusPublished - 1 Aug 2010

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Glycogen Synthase Kinases
Adrenergic Agents
Isoproterenol
Glycogen Synthase Kinase 3
Fibrosis
Phosphotransferases
Growth
Myocardial Contraction
Subcutaneous Infusions
Cardiomegaly
Stroke Volume
Serine
Hypertrophy
Heart Rate
Genotype
Phosphorylation
Pharmacology
Phenotype
Weights and Measures
Genes

Bibliographical note

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2010. For permissions please email: journals.permissions@oxfordjournals.org.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.

Keywords

  • GSK-3
  • remodelling
  • cardiac hypertrophy

Cite this

Webb, I. G., Nishino, Y., Clark, J. E., Murdoch, C., Walker, S. J., Makowski, M. R., ... Marber, M. S. (2010). Constitutive glycogen synthase kinase-3α/β activity protects against chronic β-adrenergic remodelling of the heart. Cardiovascular Research, 87(3), 494-503. https://doi.org/10.1093/cvr/cvq061
Webb, Ian G. ; Nishino, Yasuhiro ; Clark, James E. ; Murdoch, Colin ; Walker, Simon J. ; Makowski, Marcus R. ; Botnar, Rene M. ; Redwood, Simon R. ; Shah, Ajay M. ; Marber, Michael S. / Constitutive glycogen synthase kinase-3α/β activity protects against chronic β-adrenergic remodelling of the heart. In: Cardiovascular Research. 2010 ; Vol. 87, No. 3. pp. 494-503.
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Webb, IG, Nishino, Y, Clark, JE, Murdoch, C, Walker, SJ, Makowski, MR, Botnar, RM, Redwood, SR, Shah, AM & Marber, MS 2010, 'Constitutive glycogen synthase kinase-3α/β activity protects against chronic β-adrenergic remodelling of the heart' Cardiovascular Research, vol. 87, no. 3, pp. 494-503. https://doi.org/10.1093/cvr/cvq061

Constitutive glycogen synthase kinase-3α/β activity protects against chronic β-adrenergic remodelling of the heart. / Webb, Ian G.; Nishino, Yasuhiro; Clark, James E.; Murdoch, Colin; Walker, Simon J.; Makowski, Marcus R.; Botnar, Rene M.; Redwood, Simon R.; Shah, Ajay M.; Marber, Michael S.

In: Cardiovascular Research, Vol. 87, No. 3, 01.08.2010, p. 494-503.

Research output: Contribution to journalArticle

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T1 - Constitutive glycogen synthase kinase-3α/β activity protects against chronic β-adrenergic remodelling of the heart

AU - Webb, Ian G.

AU - Nishino, Yasuhiro

AU - Clark, James E.

AU - Murdoch, Colin

AU - Walker, Simon J.

AU - Makowski, Marcus R.

AU - Botnar, Rene M.

AU - Redwood, Simon R.

AU - Shah, Ajay M.

AU - Marber, Michael S.

N1 - Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2010. For permissions please email: journals.permissions@oxfordjournals.org. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.

PY - 2010/8/1

Y1 - 2010/8/1

N2 - AimsGlycogen synthase kinase 3 (GSK-3) signalling is implicated in the growth of the heart during development and in response to stress. However, its precise role remains unclear. We set out to characterize developmental growth and response to chronic isoproterenol (ISO) stress in knockin (KI) mice lacking the critical N-terminal serines, 21 of GSK-3α and 9 of GSK-3β respectively, required for inactivation by upstream kinases.Methods and resultsBetween 5 and 15 weeks, KI mice grew more rapidly, but normalized heart weight and contractile performance were similar to wild-type (WT) mice. Isolated hearts of both genotypes responded comparably to acute ISO infusion with increases in heart rate and contractility. In WT mice, chronic subcutaneous ISO infusion over 14 days resulted in cardiac hypertrophy, interstitial fibrosis, and impaired contractility, accompanied by foetal gene reactivation. These effects were all significantly attenuated in KI mice. Indeed, ISO-treated KI hearts demonstrated reversible physiological remodelling traits with increased stroke volume and a preserved contractile response to acute adrenergic stimulation. Furthermore, simultaneous pharmacological inhibition of GSK-3 in KI mice treated with chronic subcutaneous ISO recapitulated the adverse remodelling phenotype seen in WT hearts.ConclusionExpression of inactivation-resistant GSK-3α/β does not affect eutrophic myocardial growth but protects against pathological hypertrophy induced by chronic adrenergic stimulation, maintaining cardiac function and attenuating interstitial fibrosis. Accordingly, strategies to prevent phosphorylation of Ser-21/9, and consequent inactivation of GSK-3α/β, may enable a sustained cardiac response to chronic β-agonist stimulation while preventing pathological remodelling.

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KW - GSK-3

KW - remodelling

KW - cardiac hypertrophy

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