title: Endothelial Kruppel-like factor 4 protects against atherothrombosis in mice.
abstract: The endothelium regulates vascular homeostasis, and endothelial dysfunction is a proximate event in the pathogenesis of atherothrombosis. Stimulation of the endothelium with proinflammatory cytokines or exposure to hemodynamic-induced disturbed flow leads to a proadhesive and prothrombotic phenotype that promotes atherothrombosis. In contrast, exposure to arterial laminar flow induces a gene program that confers a largely antiadhesive, antithrombotic effect. The molecular basis for this differential effect on endothelial function remains poorly understood. While recent insights implicate Kruppel-like factors (KLFs) as important regulators of vascular homeostasis, the in vivo role of these factors in endothelial biology remains unproven. Here, we show that endothelial KLF4 is an essential determinant of atherogenesis and thrombosis. Using in vivo EC-specific KLF4 overexpression and knockdown murine models, we found that KLF4 induced an antiadhesive, antithrombotic state. Mechanistically, we demonstrated that KLF4 differentially regulated pertinent endothelial targets via competition for the coactivator p300. These observations provide cogent evidence implicating endothelial KLFs as essential in vivo regulators of vascular function in the adult animal.
authors.affiliation: Case Cardiovascular Research Institute, Case Western Reserve University, and University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Guangjin
authors.initials: G
authors.lastname: Zhou
authors.forename: Anne
authors.initials: A
authors.lastname: Hamik
authors.forename: Lalitha
authors.initials: L
authors.lastname: Nayak
authors.forename: Hongmei
authors.initials: H
authors.lastname: Tian
authors.forename: Hong
authors.initials: H
authors.lastname: Shi
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lu
authors.forename: Nikunj
authors.initials: N
authors.lastname: Sharma
authors.forename: Xudong
authors.initials: X
authors.lastname: Liao
authors.forename: Andrew
authors.initials: A
authors.lastname: Hale
authors.forename: Lauren
authors.initials: L
authors.lastname: Boerboom
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Feaver
authors.forename: Huiyun
authors.initials: H
authors.lastname: Gao
authors.forename: Amar
authors.initials: A
authors.lastname: Desai
authors.forename: Alvin
authors.initials: A
authors.lastname: Schmaier
authors.forename: Stanton L
authors.initials: SL
authors.lastname: Gerson
authors.forename: Yunmei
authors.initials: Y
authors.lastname: Wang
authors.forename: G Brandon
authors.initials: GB
authors.lastname: Atkins
authors.forename: Brett R
authors.initials: BR
authors.lastname: Blackman
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Simon
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D013927:Thrombosis / Q000235:genetics / Q000378:metabolism*; D014657:Vasculitis / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D050880:p300-CBP Transcription Factors