Krüppel-like factor 4 regulates pressure-induced cardiac hypertrophy.
Krüppel-like factors (KLF) are a subfamily of the zinc-finger class of transcriptional regulators that play important roles in diverse cellular processes. While a number of KLFs are expressed in cardiomyocytes, little is known about their specific roles in the heart in vivo. Here, we demonstrate that KLF4 is induced by hypertrophic stimuli in cultured cardiomyocytes and in the mouse heart. Overexpression of KLF4 in neonatal rat ventricular myocytes inhibits three cardinal features of cardiomyocyte hypertrophy: fetal gene expression, protein synthesis, and cell enlargement. Conversely, mice with cardiomyocyte-specific deletion of KLF4 (CM-K4KO) are highly sensitized to transverse aortic constriction (TAC) and exhibit high rates of mortality. CM-K4KO mice that survive TAC display severe pathologic cardiac hypertrophy characterized by increased cardiac mass, depressed LV systolic function, pulmonary congestion, cavity dilation and attenuated LV wall thickening when compared to control genotypes. In addition, CM-K4KO mice develop increased myocardial fibrosis and apoptotic cell death after TAC. Collectively, these studies implicate KLF4 as a novel transcriptional regulator that is indispensible for the heart's response to stress in vivo.
Liao
Xudong
X
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Haldar
Saptarsi M
SM
Lu
Yuan
Y
Jeyaraj
Darwin
D
Paruchuri
Kaavya
K
Nahori
Monika
M
Cui
Yingjie
Y
Kaestner
Klaus H
KH
Jain
Mukesh K
MK
D000818:Animals; D006332:Cardiomegaly / Q000150:complications / Q000378:metabolism*; D002478:Cells, Cultured; D006333:Heart Failure / Q000150:complications / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D011312:Pressure; D051381:Rats
C000715468:Klf4 protein, mouse; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors