The Kruppel-like factor KLF15 inhibits connective tissue growth factor (CTGF) expression in cardiac fibroblasts.
Cardiac fibrosis is a hallmark feature of pathologic remodeling of the heart in response to hemodynamic or neurohormonal stress. Accumulating evidence implicates connective tissue growth factor (CTGF) as a key mediator of this process. Our group has previously identified Kruppel-Like Factor 15 (KLF15) as an important regulator of cardiac remodeling in response to stress; however, the role of this transcription factor in cardiac fibrosis has not been reported. Here we provide evidence that treatment of neonatal rat ventricular fibroblasts (NRVFs) with the potent pro-fibrotic agent Transforming Growth Factor-beta1 (TGFbeta1) strongly reduces KLF15 expression while inducing the pro-fibrotic factor CTGF. Adenoviral overexpression of KLF15 inhibits basal and TGFbeta1-induced CTGF expression in NRVFs. Furthermore, hearts from KLF15-/- mice subjected to aortic banding exhibited increased CTGF levels and fibrosis. From a mechanistic standpoint, KLF15 inhibits basal and TGFbeta1-mediated induction of the CTGF promoter. Chromatin Immunoprecipitation (ChIP) and electrophoretic mobility shift assays demonstrate that KLF15 inhibits recruitment of the co-activator P/CAF to the CTGF promoter with no significant effect on Smad3-DNA binding. Consistent with this observation, KLF15 mediated repression of the CTGF promoter is rescued by P/CAF overexpression. Our result implicates KLF15 as a novel negative regulator of CTGF expression and cardiac fibrosis.
Wang
Baiqiu
B
Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine/University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
Haldar
Saptarsi M
SM
Lu
Yuan
Y
Ibrahim
Osama A
OA
Fisch
Sudeshna
S
Gray
Susan
S
Leask
Andrew
A
Jain
Mukesh K
MK
D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000502:physiology*; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
C526318:CCN2 protein, mouse; C526316:CCN2 protein, rat; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; C467418:Klf15 protein, mouse; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; D055513:Connective Tissue Growth Factor