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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2015     Display Documents

ID: 711914.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2015
Laminar shear stress inhibits endothelial cell metabolism via KLF2-mediated repression of PFKFB3
Authors:Doddaballapur, A.; Michalik, K. M.; Manavski, Y.; Lucas, T.; Houtkooper, R. H.; You, X.; Chen, W.; Zeiher, A. M.; Potente, M.; Dimmeler, S.; Boon, R. A.
Date of Publication (YYYY-MM-DD):2015-01
Title of Journal:Arterioscler Thromb Vasc Biol
Issue / Number:1
Start Page:137
End Page:145
Audience:Not Specified
Abstract / Description:OBJECTIVE: Cellular metabolism was recently shown to regulate endothelial cell phenotype profoundly. Whether the atheroprotective biomechanical stimulus elicited by laminar shear stress modulates endothelial cell metabolism is not known. APPROACH AND RESULTS: Here, we show that laminar flow exposure reduced glucose uptake and mitochondrial content in endothelium. Shear stress-mediated reduction of endothelial metabolism was reversed by silencing the flow-sensitive transcription factor Kruppel-like factor 2 (KLF2). Endothelial-specific deletion of KLF2 in mice induced glucose uptake in endothelial cells of perfused hearts. KLF2 overexpression recapitulates the inhibitory effects on endothelial glycolysis elicited by laminar flow, as measured by Seahorse flux analysis and glucose uptake measurements. RNA sequencing showed that shear stress reduced the expression of key glycolytic enzymes, such as 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3 (PFKFB3), phosphofructokinase-1, and hexokinase 2 in a KLF2-dependent manner. Moreover, KLF2 represses PFKFB3 promoter activity. PFKFB3 knockdown reduced glycolysis, and overexpression increased glycolysis and partially reversed the KLF2-mediated reduction in glycolysis. Furthermore, PFKFB3 overexpression reversed KLF2-mediated reduction in angiogenic sprouting and network formation. CONCLUSIONS: Our data demonstrate that shear stress-mediated repression of endothelial cell metabolism via KLF2 and PFKFB3 controls endothelial cell phenotype.
Free Keywords:Animals; Biomechanical Phenomena; Cells, Cultured; Down-Regulation; Endothelial Cells/*enzymology; *Energy Metabolism; Glucose/metabolism; Glycolysis; Human Umbilical Vein Endothelial Cells/enzymology; Kruppel-Like Transcription Factors/deficiency/genetics/*metabolism; *Mechanotransduction, Cellular; Mice, Knockout; Mitochondria/metabolism; Myocardium/metabolism; Neovascularization, Physiologic; Phenotype; Phosphofructokinase-2/genetics/*metabolism; Promoter Regions, Genetic; RNA Interference; Regional Blood Flow; Stress, Mechanical; Time Factors; Transfection; angiogenesis; endothelium; hemodynamics; metabolism; shear stress down regulated gene-1 protein, human
External Publication Status:published
Document Type:Article
Communicated by:MPI für Herz- und Lungenforschung
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:From the Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Goethe University, Frankfurt am Main, Germany (A.D., K.M.M., Y.M., T.L., S.D., R.A.B.); The Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands (R.H.H.); The Max-Delbruck-Center, Berlin, Germany (X.Y., W.C.); Department of Cardiology, Internal Medicine III, Goethe University Hospital Frankfurt, Frankfurt am Main, Germany (A.M.Z.); Angiogenesis and Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.P.); and German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Frankfurt am Main, Germany (A.M.Z., S.D.). boon@med.uni-frankfurt.de. %^ 1435830164
Identifiers:ISSN:1524-4636 (Electronic) 1079-5642 (Linking) %R 10.1161/ATVBAHA.114.304277
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