title: Krüppel-like factor 4 mediates histone deacetylase inhibitor-induced prevention of cardiac hypertrophy.
abstract: Recently, we reported that histone deacetylase (HDAC) inhibitors block cardiac hypertrophy and that activation of HDAC2, one of the class I HDACs, is required for hypertrophy. In the present study, we tried to find the downstream target of HDAC inhibitor by utilizing cardiomyocytes and H9c2 cells. Both trichostatin A (TSA, class I and II HDAC inhibitor) and SK7041 (SK, class I HDAC blocker) attenuated the expression level and promoter activity of Nppa (natriuretic polypeptide precursor type A) and Myh7 (myosin heavy polypeptide 7), which are fetal genes associated with hypertrophy. Promoter-mapping revealed that the Nppa promoter region from -130 to approximately -105, which contains binding sites for Krüppel-like factor 4 (KLF4), is responsible for the HDAC inhibitor-mediated inhibition. SK-induced repression of Nppa promoter activity was attenuated when the KLF4-binding element was deleted or disrupted. Klf4 was upregulated by HDAC inhibitors, whereas it was down-regulated by phenylephrine in cardiomyocytes or by partial aortic constriction in mice. Klf4 successfully recruited the proximal Nppa promoter region flanking the KLF4-binding element in cardiomyocytes, and the recruitment was reduced by treatment with phenylephrine, which was recovered by SK. Overexpression of Klf4 blocked the agonist-induced increase in cardiomyocyte size, [(3)H]-leucine incorporation, and Nppa promoter activation. However, promoter activity was not prominently inhibited when the KLF4-binding element was disrupted or when a small inhibitory RNA to KLF4 was transfected into cells. Hypertrophic phenotypes were enhanced in Klf4-knockdown cells. These results suggest that KLF4, a novel anti-hypertrophic transcriptional regulator, mediates the HDAC inhibitor-induced prevention of cardiac hypertrophy.
authors.affiliation: Department of Pharmacology and Medical Research Center for Gene Regulation, Chonnam National University Medical School, Heart Research Center of Chonnam National University Hospital, Gwangju 501-746, South Korea.
authors.forename: Hae Jin
authors.initials: HJ
authors.lastname: Kee
authors.forename: Hyun
authors.initials: H
authors.lastname: Kook
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism / Q000517:prevention & control*; D015536:Down-Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D018995:Myosin Heavy Chains; D010641:Phenotype; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D020218:Response Elements / Q000235:genetics; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D056572:Histone Deacetylase Inhibitors; C000715468:Klf4 protein, mouse; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C000594638:MYH7 protein, rat; C472610:atrial natriuretic peptide, rat; D009320:Atrial Natriuretic Factor; D018995:Myosin Heavy Chains