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| Item Type: | Article |
|---|---|
| Title: | Reoxygenation after severe hypoxia induces cardiomyocyte hypertrophy in vitro: activation of CREB downstream of GSK3beta |
| Creators Name: | El Jamali, A., Freund, C., Rechner, C., Scheidereit, C., Dietz, R. and Bergmann, M.W. |
| Abstract: | In vivo, left ventricular remodeling after myocardial infarction involves hypertrophy generally attributed to increased cardiac workload. We hypothesized that hypoxia/reoxygenation directly induces cardiomyocyte hypertrophy and studied several participating kinases and transcription factors in isolated cardiomyocytes. Hypoxia for 6 h followed by 42 h reoxygenation induced cardiomyocyte hypertrophy assessed by 3H leucine incorporation and immunohistochemistry. Inhibition of reactive oxygen species (ROS), serine/threonine kinase AKT, and ERK abolished reoxygenation-induced hypertrophy. In addition, a {beta}2-adrenergic receptor ({beta}2-AR) antagonist, as well as Gi inhibitor pertussis toxin, blocked reoxygenation-induced hypertrophy. Hypoxia for 6 h increased transcription factors CREB, NF-{kappa}B, and GATA DNA binding activities. However, only CREB DNA-binding was sustained during reoxygenation. Inhibition of PI3-kinase, ERK, and PKA abrogated reoxygenation-induced CREB DNA-binding without affecting CREB serine-133 phosphorylation. These same pathways were found to regulate hypoxia/reoxygenation-induced GSK3beta kinase activity and CREB serine-129 de-phosphorylation. GSK3{beta} mutants resistant to phosphorylation blocked the stimulation of CRE-dependent transcription induced by hypoxia/reoxygenation. Transfection of cardiomyocytes with a dominant-negative mutant of CREB abrogated hypoxia/reoxygenation-induced hypertrophy. We suggest that hypoxia/reoxygenation induces cardiomyocyte hypertrophy through CREB activation. Inactivation of GSK3{beta} by hypoxia/reoxygenation, possibly integrating PI3-kinase and ERK pathways downstream of {beta}2-AR and ROS, is a prerequisite for CRE-dependent transcription. Transient hypoxia may contribute to cardiac hypertrophy in ischemic heart disease independent of cardiac workload. |
| Keywords: | Cardiac Hypertrophy, Heart Failure, CRE-dependent transcription, Animals, Rats |
| Source: | FASEB Journal |
| ISSN: | 0892-6638 |
| Publisher: | Federation of American Societies for Experimental Biology |
| Volume: | 18 |
| Number: | 10 |
| Page Range: | 1096-1098 |
| Date: | 1 January 2004 |
| Official Publication: | https://doi.org/10.1096/fj.03-1054fje |
| PubMed: | View item in PubMed |
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