Document Detail

Defining the regulation of KLF4 expression and its downstream transcriptional targets in vascular endothelial cells.
MedLine Citation:
PMID:  19968965     Owner:  NLM     Status:  MEDLINE    
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.
Guadalupe Villarreal; Yuzhi Zhang; H Benjamin Larman; Jorge Gracia-Sancho; Andrew Koo; Guillermo García-Cardeña
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-12-05
Journal Detail:
Title:  Biochemical and biophysical research communications     Volume:  391     ISSN:  1090-2104     ISO Abbreviation:  Biochem. Biophys. Res. Commun.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2010-01-27     Completed Date:  2010-03-15     Revised Date:  2014-09-13    
Medline Journal Info:
Nlm Unique ID:  0372516     Medline TA:  Biochem Biophys Res Commun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  984-9     Citation Subset:  IM    
Copyright Information:
Copyright 2009 Elsevier Inc. All rights reserved.
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MeSH Terms
Endothelium, Vascular / drug effects,  metabolism*
Gene Expression Profiling
Gene Expression Regulation*
Genome-Wide Association Study
Kruppel-Like Transcription Factors / genetics,  metabolism*
MADS Domain Proteins / metabolism
MAP Kinase Kinase 5 / metabolism
MEF2 Transcription Factors
Mitogen-Activated Protein Kinase 7 / metabolism
Myogenic Regulatory Factors / metabolism
Shear Strength
Stilbenes / pharmacology
Grant Support
Reg. No./Substance:
0/GKLF protein; 0/KLF2 protein, human; 0/Kruppel-Like Transcription Factors; 0/MADS Domain Proteins; 0/MEF2 Transcription Factors; 0/MEF2A protein, human; 0/Myogenic Regulatory Factors; 0/Stilbenes; EC 2.7.1.-/MAP2K5 protein, human; EC Protein Kinase 7; EC Kinase Kinase 5; Q369O8926L/resveratrol

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