title: Krüppel-like Factor 13 Is a Major Mediator of Glucocorticoid Receptor Signaling in Cardiomyocytes and Protects These Cells from DNA Damage and Death.
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.
authors.affiliation: From the Laboratory of Signal Transduction and.
authors.forename: Diana
authors.initials: D
authors.lastname: Cruz-Topete
authors.affiliation: Integrative Bioinformatics, NIEHS, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709.
authors.forename: Bo
authors.initials: B
authors.lastname: He
authors.affiliation: Integrative Bioinformatics, NIEHS, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709.
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Xu
authors.affiliation: From the Laboratory of Signal Transduction and cidlows1@niehs.nih.gov.
authors.forename: John A
authors.initials: JA
authors.lastname: Cidlowski
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D003035:Cobalt / Q000009:adverse effects / Q000494:pharmacology; D004249:DNA Damage; D004317:Doxorubicin / Q000009:adverse effects / Q000494:pharmacology; D006333:Heart Failure / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction
chemical_list: D018797:Cell Cycle Proteins; C486422:Klf13 protein, mouse; D051741:Kruppel-Like Transcription Factors; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D003035:Cobalt; D004317:Doxorubicin; C018021:cobaltous chloride
keywords: Kruppel-like factor (KLF); cardiomyocyte; gene regulation; glucocorticoid receptor; hypoxia