Transcription Factor 7-like 2 Mediates Canonical Wnt/β-Catenin Signaling and c-Myc Upregulation in Heart Failure
| العنوان: | Transcription Factor 7-like 2 Mediates Canonical Wnt/β-Catenin Signaling and c-Myc Upregulation in Heart Failure |
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| المؤلفون: | Haodong Xu, Ning Hou, Bo Ye, Xuejun Wang, Kenneth B. Margulies, Xiang Li, Faqian Li |
| المصدر: | Circulation: Heart Failure. 9 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Adult, Cardiomyopathy, Dilated, Male, 0301 basic medicine, medicine.medical_specialty, Transcription, Genetic, Cardiomyopathy, 030204 cardiovascular system & hematology, Biology, Transfection, Proto-Oncogene Mas, Transcription Factor 7-Like 2, Article, Desmin, Proto-Oncogene Proteins c-myc, Rats, Sprague-Dawley, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Idiopathic dilated cardiomyopathy, medicine, Animals, Humans, Promoter Regions, Genetic, Histone H3 acetylation, Wnt Signaling Pathway, Transcription factor, Cells, Cultured, beta Catenin, Heart Failure, Mice, Knockout, Binding Sites, Wnt signaling pathway, LRP5, Middle Aged, medicine.disease, Up-Regulation, Cell biology, Disease Models, Animal, 030104 developmental biology, Endocrinology, Female, RNA Interference, Cardiology and Cardiovascular Medicine, Transcription Factor 7-Like 2 Protein, Chromatin immunoprecipitation |
| الوصف: | Background— How canonical Wnt/β-catenin signals in adult hearts, especially in different diseased states, remains unclear. The proto-oncogene, c-Myc, is a Wnt target and an early response gene during cardiac stress. It is not clear whether c-Myc is activated or how it is regulated during heart failure. Methods and Results— We investigated canonical Wnt/β-catenin signaling and how it regulated c-Myc expression in failing hearts of human ischemic heart disease, idiopathic dilated cardiomyopathy, and murine desmin–related cardiomyopathy. Our data demonstrated that canonical Wnt/β-catenin signaling was activated through nuclear accumulation of β-catenin in idiopathic dilated cardiomyopathy, ischemic heart disease, and murine desmin–related cardiomyopathy when compared with nonfailing controls and transcription factor 7-like 2 (TCF7L2) was the main β-catenin partner of the T-cell factor (TCF) family in adult hearts. We further revealed that c-Myc mRNA and protein levels were significantly elevated in failing hearts by real-time reverse transcription polymerase chain reaction, Western blotting, and immunohistochemical staining. Immunoprecipitation and confocal microscopy further showed that β-catenin interacted and colocalized with TCF7L2. More importantly, chromatin immunoprecipitation confirmed that β-catenin and TCF7L2 were recruited to the regulatory elements of c-Myc. This recruitment was associated with increased histone H3 acetylation and transcriptional upregulation of c-Myc. With lentiviral infection, TCF7L2 overexpression increased c-Myc expression and cardiomyocyte size, whereas shRNA-mediated knockdown of TCF7L2 suppressed c-Myc expression and cardiomyocyte growth in cultured neonatal rat cardiomyocytes. Conclusions— This study indicates that TCF7L2 mediates canonic Wnt/β-catenin signaling and c-Myc upregulation during abnormal cardiac remodeling in heart failure and suppression of Wnt/β-catenin to c-Myc axis can be explored for preventing and treating heart failure. |
| تدمد: | 1941-3297 1941-3289 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6daf2af244485e07e591948392e9def2Test https://doi.org/10.1161/circheartfailure.116.003010Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6daf2af244485e07e591948392e9def2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19413297 19413289 |
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