Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy.
Cardiac hypertrophy is a common response to injury and hemodynamic stress and an important harbinger of heart failure and death. Herein, we identify the Kruppel-like factor 15 (KLF15) as an inhibitor of cardiac hypertrophy. Myocardial expression of KLF15 is reduced in rodent models of hypertrophy and in biopsy samples from patients with pressure-overload induced by chronic valvular aortic stenosis. Overexpression of KLF15 in neonatal rat ventricular cardiomyocytes inhibits cell size, protein synthesis and hypertrophic gene expression. KLF15-null mice are viable but, in response to pressure overload, develop an eccentric form of cardiac hypertrophy characterized by increased heart weight, exaggerated expression of hypertrophic genes, left ventricular cavity dilatation with increased myocyte size, and reduced left ventricular systolic function. Mechanistically, a combination of promoter analyses and gel-shift studies suggest that KLF15 can inhibit GATA4 and myocyte enhancer factor 2 function. These studies identify KLF15 as part of a heretofore unrecognized pathway regulating the cardiac response to hemodynamic stress.
Fisch
Sudeshna
S
Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, 2103 Cornell Road, Room 4-503, Cleveland, OH 44106, USA.
Gray
Susan
S
Heymans
Stephane
S
Haldar
Saptarsi M
SM
Wang
Baiqiu
B
Pfister
Otmar
O
Cui
Lei
L
Kumar
Ajay
A
Lin
Zhiyong
Z
Sen-Banerjee
Sucharita
S
Das
Hiranmoy
H
Petersen
Christine A
CA
Mende
Ulrike
U
Burleigh
Barbara A
BA
Zhu
Yan
Y
Pinto
Yigal M
YM
Pinto
Yigal
Y
Liao
Ronglih
R
Jain
Mukesh K
MK
D000818:Animals; D001794:Blood Pressure; D048429:Cell Size; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D050991:GATA4 Transcription Factor / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018390:Gene Targeting; D006801:Humans; D006984:Hypertrophy; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011995:Recombination, Genetic / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; C414172:KLF15 protein, human; C467418:Klf15 protein, mouse; C520013:Klf15 protein, rat; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors