title: Erk5 activation elicits a vasoprotective endothelial phenotype via induction of Kruppel-like factor 4 (KLF4).
abstract: The MEK5/Erk5 MAPK cascade has recently been implicated in the regulation of endothelial integrity and represents a candidate pathway mediating the beneficial effects of laminar flow, a major factor preventing vascular dysfunction and disease. Here we expressed a constitutively active mutant of MEK5 (MEK5D) to study the transcriptional and functional responses to Erk5 activation in human primary endothelial cells. We provide evidence that constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential. This is supported by bioinformatic microarray analysis, which uncovered a statistical overrepresentation of corresponding functional clusters as well as a significant induction of anti-thrombotic, hemostatic, and vasodilatory genes. We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5. We show that KLF4 expression largely reproduces the protective phenotype in endothelial cells, whereas KLF4 siRNA suppresses expression of various Erk5 targets. Additionally, we show that vasoprotective statins potently induce KLF4 and KLF4-dependent gene expression via activation of Erk5. Our data underscore a major protective function of the MEK5/Erk5/KLF4 module in ECs and implicate agonistic Erk5 activation as potential strategy for treatment of vascular diseases.
authors.affiliation: Department of Dermatology, University Hospital Mannheim, University of Heidelberg, Mannheim 68167, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Ohnesorge
authors.forename: Dorothee
authors.initials: D
authors.lastname: Viemann
authors.forename: Nicole
authors.initials: N
authors.lastname: Schmidt
authors.forename: Tobias
authors.initials: T
authors.lastname: Czymai
authors.forename: Désirée
authors.initials: D
authors.lastname: Spiering
authors.forename: Mirco
authors.initials: M
authors.lastname: Schmolke
authors.forename: Stephan
authors.initials: S
authors.lastname: Ludwig
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.forename: Matthias
authors.initials: M
authors.lastname: Goebeler
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt
mesh_terms: D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation; D006487:Hemostasis / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D048671:MAP Kinase Kinase 5 / Q000378:metabolism*; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D020011:Protective Agents; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation; D014664:Vasodilation / Q000235:genetics
chemical_list: C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D020011:Protective Agents; D048054:Mitogen-Activated Protein Kinase 7; D048671:MAP Kinase Kinase 5; C482563:MAP2K5 protein, human