GSK-3β heterozygous knockout is cardioprotective in a knockin mouse model of familial dilated cardiomyopathy

Rasha M.S.M. Mohamed, Sachio Morimoto, Islam A.A.E.H. Ibrahim, Dong Yun Zhan, Cheng Kun Du, Masaki Arioka, Tatsuya Yoshihara, Fumi Takahashi-Yanaga, Toshiyuki Sasaguri

Research output: Contribution to journalArticle

Abstract

Glycogen synthase kinase-3β (GSK-3β) plays a central role in both cardiac physiology and pathology. Herein we want to clarify the role of GSK-3β in familial dilated cardiomyopathy. We generated a mouse model carrying a heterozygous knockout mutation of GSK-3β (GSK-3β+/−KO), together with a ΔK210 knockin mutation in cardiac troponin T (ΔK210 cTnT KI), which was proved to be one of the genetic causes of familial dilated cardiomyopathy (DCM). GSK-3β+/−KO prevented the slow and rapid deterioration in left ventricular systolic function accompanying heart failure (HF) in DCM mice with heterozygous and homozygous ΔK210 cTnT KI mutations, respectively. GSK-3β+/−KO also prevented cardiac enlargement, myocardial fibrosis, and cardiomyocyte apoptosis and markedly reduced the expression of cardiac β-myosin heavy chain isoform, indicative of HF, in DCM mice with homozygous ΔK210 cTnT KI mutation. GSK-3β+/−KO also extended the life span of these DCM mice. This study suggests that the inhibition of GSK-3β is cardioprotective in familial DCM associated with ΔK210 cTnT mutation.

Original languageEnglish
Pages (from-to)H1808-H1815
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume310
Issue number11
DOIs
Publication statusPublished - Jun 2016

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Glycogen Synthase Kinase 3
Dilated Cardiomyopathy
Mutation
Heart Failure
Cardiac Myosins
Troponin T
Myosin Heavy Chains
Familial dilated cardiomyopathy
Left Ventricular Function
Cardiac Myocytes
Protein Isoforms
Fibrosis
Apoptosis
Pathology

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

GSK-3β heterozygous knockout is cardioprotective in a knockin mouse model of familial dilated cardiomyopathy. / Mohamed, Rasha M.S.M.; Morimoto, Sachio; Ibrahim, Islam A.A.E.H.; Zhan, Dong Yun; Du, Cheng Kun; Arioka, Masaki; Yoshihara, Tatsuya; Takahashi-Yanaga, Fumi; Sasaguri, Toshiyuki.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 310, No. 11, 06.2016, p. H1808-H1815.

Research output: Contribution to journalArticle

Mohamed, Rasha M.S.M. ; Morimoto, Sachio ; Ibrahim, Islam A.A.E.H. ; Zhan, Dong Yun ; Du, Cheng Kun ; Arioka, Masaki ; Yoshihara, Tatsuya ; Takahashi-Yanaga, Fumi ; Sasaguri, Toshiyuki. / GSK-3β heterozygous knockout is cardioprotective in a knockin mouse model of familial dilated cardiomyopathy. In: American Journal of Physiology - Heart and Circulatory Physiology. 2016 ; Vol. 310, No. 11. pp. H1808-H1815.
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