Krüppel-like Factor 13 Is a Major Mediator of Glucocorticoid Receptor Signaling in Cardiomyocytes and Protects These Cells from DNA Damage and Death *
- From the ‡Laboratory of Signal Transduction and
- §Integrative Bioinformatics, NIEHS, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709
- ↵2 To whom correspondence should be addressed: NIEHS, National Institutes of Health MD F3-07, 111 TW Alexander Dr., Research Triangle Park, NC 27709. Tel.: 919-541-1564; Fax: 919-541-1367; E-mail: cidlows1{at}niehs.nih.gov.
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↵1 Both authors contributed equally to the results of this work.
Abstract
Glucocorticoid receptor (GR) signaling has recently been shown to play a direct role in the regulation of cardiomyocyte function. In this study, we investigated the potential role of KLF13 as a downstream effector of GR action utilizing both in vivo and in vitro approaches. Our data show that KLF13 mRNA and protein levels are significantly diminished in the hearts of mice lacking GR in cardiomyocytes. Glucocorticoid administration up-regulated Klf13 mRNA in the mouse heart, in isolated primary cardiomyocytes, and in immortal cardiomyocyte cell lines. Glucocorticoid Klf13 gene expression was abolished by treatment with a GR antagonist (RU486) or by knockdown of GR in cardiomyocytes. Moreover, glucocorticoid induction of Klf13 mRNA was resistant to de novo protein synthesis inhibition, demonstrating that Klf13 is a direct glucocorticoid receptor gene target. A glucocorticoid responsive element (GRE) was identified in the Klf13 gene and its function was verified by chromatin immunoprecipitation in HL-1 cells and mouse hearts. Functional studies showed that GR regulation of Klf13 is critical to protect cardiomyocytes from DNA damage and cell death induced by cobalt(II) chloride hexahydrate (CoCl2·6H2O) and the antineoplastic drug doxorubicin. These results established a novel role for GR and KLF13 signaling in adult cardiomyocytes with potential clinical implications for the prevention of cardiotoxicity induced heart failure.
Footnotes
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↵* This work was supported by the Intramural Research Program of the National Institutes of Health, NIEHS. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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This article contains supplemental Tables S1–S7.
- Received March 6, 2016.
- Revision received July 21, 2016.
- © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
