title: Kruppel-like factor 2 (KLF2) regulates endothelial thrombotic function.
abstract: The vascular endothelium maintains blood fluidity by inhibiting blood coagulation, inhibiting platelet aggregation, and promoting fibrinolysis. Endothelial cells lose these nonthrombogenic properties on exposure to proinflammatory stimuli. We recently identified the Kruppel-like factor KLF2 as a novel regulator of endothelial proinflammatory activation. Here it is found that KLF2 differentially regulates key factors involved in maintaining an antithrombotic endothelial surface. Overexpression of KLF2 strongly induced thrombomodulin (TM) and endothelial nitric oxide synthase (eNOS) expression and reduced plasminogen activator inhibitor-1 (PAI-1) expression. Furthermore, overexpression of KLF2 inhibited the cytokine-mediated induction of tissue factor (TF). In contrast, siRNA mediated knockdown of KLF2 reduced antithrombotic gene expression while inducing the expression of pro-coagulant factors. The functional importance of KLF2 was verified by in vitro clotting assays. By comparison to control infected cells, KLF2 overexpression increased blood clotting time as well as flow rates under basal and inflammatory conditions. In contrast, siRNA-mediated knockdown of KLF2 reduced blood clotting time and flow rates. These observations identify KLF2 as a novel transcriptional regulator of endothelial thrombotic function. The full text of this article is available online at http://circres.ahajournals.org.
authors.affiliation: Program in Cardiovascular Transcriptional Biology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02115, USA.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Lin
authors.forename: Ajay
authors.initials: A
authors.lastname: Kumar
authors.forename: Sucharita
authors.initials: S
authors.lastname: SenBanerjee
authors.forename: Kristine
authors.initials: K
authors.lastname: Staniszewski
authors.forename: Kush
authors.initials: K
authors.lastname: Parmar
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Vaughan
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gimbrone
authors.forename: Viji
authors.initials: V
authors.lastname: Balasubramanian
authors.forename: Guillermo
authors.initials: G
authors.lastname: García-Cardeña
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
mesh_terms: D000818:Animals; D001011:Aorta; D001665:Binding Sites; D001777:Blood Coagulation / Q000235:genetics / Q000502:physiology; D002417:Cattle; D002478:Cells, Cultured / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D018056:Hemorheology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D051741:Kruppel-Like Transcription Factors; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013917:Thrombin / Q000494:pharmacology; D018180:Thrombomodulin / Q000096:biosynthesis / Q000235:genetics; D013925:Thromboplastin / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism*; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins; D014841:von Willebrand Factor / Q000096:biosynthesis / Q000235:genetics
chemical_list: D018076:DNA, Complementary; D007375:Interleukin-1; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D018180:Thrombomodulin; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D014841:von Willebrand Factor; D013925:Thromboplastin; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D013917:Thrombin