Inhibition of glycogen synthase kinase-3β prevents sympathetic hyperinnervation in infarcted rats

Tsung-Ming Lee, Shinn Zong Lin, Nen Chung Chang

Research output: Contribution to journalArticle

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Abstract

We have demonstrated that nerve growth factor (NGF) expression in the myocardium is selectively increased during chronic stage of myocardial infarction, resulting in sympathetic hyperinnervation. Glycogen synthase kinase-3 (GSK-3) signal has been shown to play key roles in the regulation of cytoskeletal assembly during axon regeneration. We assessed whether lithium, a GSK-3 inhibitor, attenuates cardiac sympathetic reinnervation after myocardial infarction through attenuated NGF expression and Tau expression. Twenty-four hours after ligation of the anterior descending artery, male Wistar rats were randomized to either LiCl or SB216763, chemically unrelated inhibitors of GSK-3β, a combination of LiCl and SB216763, or vehicle for four weeks. Myocardial norepinephrine levels revealed a significant elevation in vehicle-treated rats compared with sham-operated rats, consistent with excessive sympathetic reinnervation after infarction. Immunohistochemical analysis for sympathetic nerve also confirmed the change of myocardial norepinephrine. This was paralleled by a significant upregulation of NGF protein and mRNA in the vehicle-treated rats, which was reduced after administering either LiCl, SB216763, or combination. Arrhythmic scores during programmed stimulation in the vehicle-treated rats were significantly higher than those treated with GSK-3 inhibitors. Addition of SB216763 did not have additional beneficial effects compared with those seen in rats treated with LiCl alone. Furthermore, lithium treatment increased Tau1 and decreased AT8 and AT180 levels. Chronic use of lithium after infarction, resulting in attenuated sympathetic reinnervation by GSK-3 inhibition, may modify the arrhythmogenic response to programmed electrical stimulation.

Original languageEnglish
Pages (from-to)979-992
Number of pages14
JournalExperimental Biology and Medicine
Volume240
Issue number7
DOIs
Publication statusPublished - Jul 14 2015

Fingerprint

Glycogen Synthase Kinase 3
Rats
Nerve Growth Factor
Lithium
Infarction
Norepinephrine
Myocardial Infarction
Electric Stimulation
Ligation
Axons
Wistar Rats
Regeneration
Myocardium
Up-Regulation
Arteries
Messenger RNA
SB 216763
Proteins

Keywords

  • Arrhythmias
  • glycogen synthase kinase-3
  • lithium
  • myocardial infarction
  • Tau protein

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Inhibition of glycogen synthase kinase-3β prevents sympathetic hyperinnervation in infarcted rats. / Lee, Tsung-Ming; Lin, Shinn Zong; Chang, Nen Chung.

In: Experimental Biology and Medicine, Vol. 240, No. 7, 14.07.2015, p. 979-992.

Research output: Contribution to journalArticle

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