Slow progressive conduction and contraction defects in loss of Nkx2–5 mice after cardiomyocyte terminal differentiation
| Autor: | Sonisha Warren, Kenneth R. Chien, Jonathan T. Lu, Hiroko Wakimoto, Hideko Kasahara, Melissa H Marks, Keith D. Robertson, Laura E Briggs, Morihiko Takeda, Ellen O. Weinberg |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Male
medicine.medical_specialty Contraction (grammar) Heart disease Down-Regulation Cardiomegaly 030204 cardiovascular system & hematology Biology Article Pathology and Forensic Medicine Muscle hypertrophy 03 medical and health sciences Electrocardiography Mice 0302 clinical medicine stomatognathic system Heart Conduction System Internal medicine medicine Animals Telemetry Myocytes Cardiac Molecular Biology 030304 developmental biology Homeodomain Proteins Mice Knockout 0303 health sciences medicine.diagnostic_test Cell Differentiation Cell Biology medicine.disease Myocardial Contraction Cardiovascular physiology Endocrinology cardiovascular system Homeobox Protein Nkx-2.5 Female Heart enlargement Electrical conduction system of the heart Cardiomyopathies Atrioventricular block Transcription Factors |
| Zdroj: | Laboratory investigation; a journal of technical methods and pathology |
| ISSN: | 1530-0307 0023-6837 |
| Popis: | Mutations in homeoprotein NKX2-5 are linked to human congenital heart disease, resulting in various cardiac anomalies, as well as in postnatal progressive conduction defects and occasional left ventricular dysfunction; yet the function of Nkx2-5 in the postnatal period is largely unexplored. In the heart, the majority of cardiomyocytes are believed to complete cell-cycle withdrawal shortly after birth, which is generally accompanied by a re-organization of chromatin structure shown in other tissues. We reasoned that the effects of the loss of Nkx2-5 in mice may be different after cell-cycle withdrawal compared with those of the perinatal loss of Nkx2-5, which results in rapid conduction and contraction defects within 4 days after the deletion of Nkx2-5 alleles (Circ Res. 2008;103:580). In this study, floxed-Nkx2-5 alleles were deleted using tamoxifen-inducible Cre transgene (Cre-ER) beginning at 2 weeks of age. The loss of Nkx2-5 beginning at 2 weeks of age resulted in conduction and contraction defects similar to the perinatal loss of Nkx2-5, however, with a substantially slower disease progression shown by 1 degrees atrioventricular block at 6 weeks of age (4 weeks after tamoxifen injections) and heart enlargement after 12 weeks of age (10 weeks after tamoxifen injections). The phenotypes were accompanied by a slower and smaller degree of reduction of several critical Nkx2-5 downstream targets that were observed in mice with a perinatal loss of Nkx2-5. These results suggest that Nkx2-5 is necessary for proper conduction and contraction after 2 weeks of age, but with a substantially distinct level of necessity at 2 weeks of age compared with that in the perinatal period. |
| Databáze: | OpenAIRE |
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