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

被引:25
作者
Webb, Ian G. [1 ]
Nishino, Yasuhiro [1 ]
Clark, James E. [1 ]
Murdoch, Colin [1 ]
Walker, Simon J. [1 ]
Makowski, Marcus R. [2 ]
Botnar, Rene M. [2 ]
Redwood, Simon R. [1 ]
Shah, Ajay M. [1 ]
Marber, Michael S. [1 ]
机构
[1] St Thomas Hosp, Div Cardiol, Kings Coll London, BHF Ctr,Rayne Inst, London SE1 7EH, England
[2] St Thomas Hosp, Rayne Inst, Div Imaging Sci, Kings Coll London,BHF Ctr, London SE1 7EH, England
基金
英国惠康基金;
关键词
GSK-3; Cardiac hypertrophy; Remodelling; CARDIAC-HYPERTROPHY; PRESSURE-OVERLOAD; ATHLETES HEART; MESSENGER-RNA; KINASE-3-BETA; PHOSPHORYLATION; MYOCYTES; GROWTH; INHIBITION; MYOSIN;
D O I
10.1093/cvr/cvq061
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-3 alpha and 9 of GSK-3 beta respectively, required for inactivation by upstream kinases. 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. Expression of inactivation-resistant GSK-3 alpha/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-3 alpha/beta, may enable a sustained cardiac response to chronic beta-agonist stimulation while preventing pathological remodelling.
引用
收藏
页码:494 / 503
页数:10
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