Krüppel-like factor 4 mediates histone deacetylase inhibitor-induced prevention of cardiac hypertrophy.
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.
Kee
Hae Jin
HJ
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.
Kook
Hyun
H
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
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