Constitutive glycogen synthase kinase-3alpha/beta activity protects against chronic beta-adrenergic remodelling of the heart.

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-3alpha and 9 of GSK-3beta 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-3alpha/beta 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-3alpha/beta, may enable a sustained cardiac response to chronic beta-agonist stimulation while preventing pathological remodelling.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Webb IG,Nishino Y,Clark JE,Murdoch C,Walker SJ,Makowski MR,Botnar RM,Redwood SR,Shah AM,Marber MS

doi

10.1093/cvr/cvq061

subject

Has Abstract

pub_date

2010-08-01 00:00:00

pages

494-503

issue

3

eissn

0008-6363

issn

1755-3245

pii

cvq061

journal_volume

87

pub_type

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