GSK-3β heterozygous knockout is cardioprotective in a knockin mouse model of familial dilated cardiomyopathy
| Autor: | Masaki Arioka, Tatsuya Yoshihara, Rasha M. S. M. Mohamed, Toshiyuki Sasaguri, Cheng-Kun Du, Dong Yun Zhan, Sachio Morimoto, Islam A.A.E.-H. Ibrahim, Fumi Takahashi-Yanaga |
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| Rok vydání: | 2016 |
| Předmět: |
Cardiomyopathy
Dilated 0301 basic medicine medicine.medical_specialty Physiology Mice Transgenic macromolecular substances 030204 cardiovascular system & hematology Mice Ventricular Dysfunction Left 03 medical and health sciences 0302 clinical medicine Troponin T Troponin complex Physiology (medical) Internal medicine medicine Animals Glycogen synthase GSK3B Gene knockout Glycogen Synthase Kinase 3 beta Myosin Heavy Chains biology business.industry Myocardium Dilated cardiomyopathy medicine.disease Disease Models Animal 030104 developmental biology Endocrinology Heart failure cardiovascular system biology.protein Myocardial fibrosis Cardiology and Cardiovascular Medicine business Proto-Oncogene Proteins c-akt |
| Zdroj: | American Journal of Physiology-Heart and Circulatory Physiology. 310:H1808-H1815 |
| ISSN: | 1522-1539 0363-6135 |
| DOI: | 10.1152/ajpheart.00771.2015 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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