title: Defining the regulation of KLF4 expression and its downstream transcriptional targets in vascular endothelial cells.
abstract: 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.
authors.affiliation: Laboratory for Systems Biology, Center for Excellence in Vascular Biology, Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Villarreal
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Zhang
authors.forename: H Benjamin
authors.initials: HB
authors.lastname: Larman
authors.forename: Jorge
authors.initials: J
authors.lastname: Gracia-Sancho
authors.forename: Andrew
authors.initials: A
authors.lastname: Koo
authors.forename: Guillermo
authors.initials: G
authors.lastname: García-Cardeña
mesh_terms: D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D026161:MADS Domain Proteins / Q000378:metabolism; D048671:MAP Kinase Kinase 5 / Q000378:metabolism; D064326:MEF2 Transcription Factors; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D000077185:Resveratrol; D033081:Shear Strength; D013267:Stilbenes / Q000494:pharmacology
chemical_list: C096161:KLF2 protein, human; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; D018006:Myogenic Regulatory Factors; D013267:Stilbenes; D048054:Mitogen-Activated Protein Kinase 7; D048671:MAP Kinase Kinase 5; C482563:MAP2K5 protein, human; D000077185:Resveratrol