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| Status |
Public on Oct 01, 2011 |
| Title |
Genome-wide analysis of induced expression of TBX3 in the atrial appendage of the heart and controls. |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
to study the effect of induced expression of TBX3 within the atrium of the heart
Background: Treatment of congenital or acquired disorders of the sinus node or atrioventricular node requires insight into the molecular mechanisms for the development and homeostasis of these pacemaker tissues. In the developing heart, transcription factor TBX3 is required for pacemaker and conduction system development. Here, we explore the role of TBX3 in the adult heart and investigate whether TBX3 is able to reprogram terminally differentiated working cardiomyocytes into pacemaker cells. This would be an attractive approach in biological pacemaker formation. Methods and results: TBX3 expression was ectopically induced in cardiomyocytes of adult transgenic mice. Expression analysis revealed an efficient switch from the working myocardial expression profile to that of the pacemaker myocardium. This included suppression of genes encoding gap junction subunits (Cx40, Cx43), the cardiac Na+ channel (NaV1.5; INa) and inwardly rectifying K+ ion channels (Kir-genes; IK1). Concordantly, we observed conduction slowing in these hearts, and reductions in INa and IK1 in cardiomyocytes isolated from these hearts. The reduction in IK1 resulted in a more depolarized maximum diastolic potential, thus enabling spontaneous diastolic depolarization. Neither ectopic pacemaker activity nor pacemaker current, If, were observed. Lentiviral expression of TBX3 in ventricular cardiomyocytes resulted in conduction slowing and development of heterogeneous phenotypes, including depolarized and spontaneously active cardiomyocytes. Conclusions: TBX3 partially reprograms terminally differentiated working cardiomyocytes into pacemaker-like cells and induces important pacemaker properties. The ability of TBX3 to reduce intercellular coupling to overcome current-to-load mismatch and the ability to reduce IK1 density to enable diastolic depolarization, are very promising TBX3 characteristics for biological pacemaker formation strategies.
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| Overall design |
5 TBX3 expressing left atrial appendage samples (Tamoxifen-treated Myh6MCM;CTBX3 adult male mice) and 6 controls ((Tamoxifen-treated Myh6MCM adult male mice)
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| Contributor(s) |
Bakker ML, Christoffels VM, Buermans HP, 't Hoen PA |
| Citation(s) |
22419669 |
| Submission date |
Sep 07, 2011 |
| Last update date |
Jan 16, 2019 |
| Contact name |
Martijn Bakker |
| E-mail(s) |
m.l.bakker@amc.nl
|
| Organization name |
academic medical center
|
| Department |
heart failure research center
|
| Street address |
meibergdreef 15
|
| City |
amsterdam |
| State/province |
NH |
| ZIP/Postal code |
1056GT |
| Country |
Netherlands |
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| Platforms (1) |
| GPL6887 |
Illumina MouseWG-6 v2.0 expression beadchip |
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| Samples (11)
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| Relations |
| BioProject |
PRJNA144973 |
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