GSK-3β heterozygous knockout is cardioprotective in a knockin mouse model of familial dilated cardiomyopathy.
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.
Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Clinical Pharmacology, Faculty of Medicine, Zagazig University, Zagazig, Egypt;
Rasha M S M
RM
Mohamed
Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; morimoto@med.kyushu-u.ac.jp.
Sachio
S
Morimoto
Department of Pharmacology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt; and.
Islam A A E-H
IA
Ibrahim
Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
Dong-Yun
DY
Zhan
Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
Cheng-Kun
CK
Du
Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
Masaki
M
Arioka
Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
Tatsuya
T
Yoshihara
Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
Fumi
F
Takahashi-Yanaga
Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
Toshiyuki
T
Sasaguri
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020107:Troponin T / Q000235:genetics* / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000235:genetics* / Q000378:metabolism
D020107:Troponin T; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D018995:Myosin Heavy Chains
dilated cardiomyopathy; glycogen synthase kinase-3β; myocardial remodeling; survival; systolic function