TY - JOUR
T1 - Defining the regulation of KLF4 expression and its downstream transcriptional targets in vascular endothelial cells
AU - Villarreal, Guadalupe
AU - Zhang, Yuzhi
AU - Larman, H. Benjamin
AU - Gracia-Sancho, Jorge
AU - Koo, Andrew
AU - García-Cardeña, Guillermo
N1 - Funding Information:
This work was supported by the National Institutes of Health [HL-076686 and HL-090856 to G.G.-C.]; the Howard Hughes Medical Institute Research Training Fellowship for Medical Students [G.V.]; the American Federation for Aging Research/National Institute on Aging [T35 AG026781 to G.V.]; the Department of Innovation, Universities and Enterprise, Government of Catalonia, Spain, and the Spanish Association for the Study of the Liver [J.G.-S.].
PY - 2010/1/1
Y1 - 2010/1/1
N2 - The Kruppel-like factor 2 (KLF2) and Kruppel-like factor 4 (KLF4) transcription factors have recently been shown to act as critical regulators of endothelial homeostasis. While several insights have been made into the signaling mechanisms orchestrating endothelial KLF2 expression, those governing the expression of KLF4 in the vascular endothelium remain largely unknown. Here, we show that diverse vasoprotective stimuli including an atheroprotective shear stress waveform, simvastatin, and resveratrol induce the expression of KLF4 in cultured human endothelial cells. We further demonstrate that the induction of KLF4 by resveratrol and atheroprotective shear stress occurs via a MEK5/MEF2-dependent signaling pathway. Since MEK5 activation is also critical for the expression of KLF2, we assessed the individual contribution of KLF4 and KLF2 to the global transcriptional activity triggered by MEK5 activation. Genome-wide transcriptional profiling of endothelial cells overexpressing KLF4, KLF2, or constitutively active MEK5 revealed that 59.2% of the genes regulated by the activation of MEK5 were similarly controlled by either KLF2 or KLF4. Collectively, our data identify a significant degree of mechanistic and functional conservation between KLF2 and KLF4, and importantly, provide further insights into the complex regulatory networks governing endothelial vasoprotection.
AB - The Kruppel-like factor 2 (KLF2) and Kruppel-like factor 4 (KLF4) transcription factors have recently been shown to act as critical regulators of endothelial homeostasis. While several insights have been made into the signaling mechanisms orchestrating endothelial KLF2 expression, those governing the expression of KLF4 in the vascular endothelium remain largely unknown. Here, we show that diverse vasoprotective stimuli including an atheroprotective shear stress waveform, simvastatin, and resveratrol induce the expression of KLF4 in cultured human endothelial cells. We further demonstrate that the induction of KLF4 by resveratrol and atheroprotective shear stress occurs via a MEK5/MEF2-dependent signaling pathway. Since MEK5 activation is also critical for the expression of KLF2, we assessed the individual contribution of KLF4 and KLF2 to the global transcriptional activity triggered by MEK5 activation. Genome-wide transcriptional profiling of endothelial cells overexpressing KLF4, KLF2, or constitutively active MEK5 revealed that 59.2% of the genes regulated by the activation of MEK5 were similarly controlled by either KLF2 or KLF4. Collectively, our data identify a significant degree of mechanistic and functional conservation between KLF2 and KLF4, and importantly, provide further insights into the complex regulatory networks governing endothelial vasoprotection.
KW - Endothelial cells
KW - KLF2
KW - KLF4
KW - MEK5
KW - Resveratrol
KW - Shear stress
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U2 - 10.1016/j.bbrc.2009.12.002
DO - 10.1016/j.bbrc.2009.12.002
M3 - Article
C2 - 19968965
AN - SCOPUS:73149110581
SN - 0006-291X
VL - 391
SP - 984
EP - 989
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -