title: Regulation of the endothelial apelin/APJ system by hemodynamic fluid flow.
abstract: Although the apelin/APJ system is abundantly expressed in vascular endothelial cells (EC), it has not yet been considered to be regulated by fluid flow. The aim of this study was to explore the influence of shear stress on the expression of apelin/APJ in human EC. Therefore, gene and protein expression were assessed after flow exposure; cell supernatants were collected for measurements of NO and apelin; APJ or apelin knockdown were performed using siRNA. Our data show that gene and protein expression of apelin and APJ are modulated by fluid flow depending on the magnitude of shear stress. Moreover, apelin-12 activated NO production via PI3K/Akt signaling in human EC. In contrast, apelin-13 additionally activated Erk1/2 phosphorylation and enhanced EC proliferation. Knockdown of APJ inhibited phosphorylation of PI3K and impaired flow-induced eNOS and PECAM-1 expression. Knockdown of apelin had no influence on flow-induced APJ and PECAM-1 expression, but derogated eNOS expression under static and flow conditions. The present study reveals a flow-mediated adjustment of the apelin/APJ system in human EC in which APJ expression is induced by shear stress independently of its ligand. Furthermore, apelin-12 signaling is an essential regulatory element in endothelial NO synthesis.
authors: Department of Internal Medicine B (Cardiology), University Medicine Greifswald, Ferdinand-Sauerbruch-Strasse, 17475 Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Greifswald, Germany. Electronic address: buschr@uni-greifswald.de.
authors: Raila
authors: R
authors: Busch
authors: Department of Internal Medicine B (Cardiology), University Medicine Greifswald, Ferdinand-Sauerbruch-Strasse, 17475 Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Greifswald, Germany.
authors: Anne
authors: A
authors: Strohbach
authors: Department of Internal Medicine B (Cardiology), University Medicine Greifswald, Ferdinand-Sauerbruch-Strasse, 17475 Greifswald, Germany.
authors: Malte
authors: M
authors: Pennewitz
authors: Department of Internal Medicine B (Cardiology), University Medicine Greifswald, Ferdinand-Sauerbruch-Strasse, 17475 Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Greifswald, Germany.
authors: Florian
authors: F
authors: Lorenz
authors: Department of Internal Medicine B (Cardiology), University Medicine Greifswald, Ferdinand-Sauerbruch-Strasse, 17475 Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Greifswald, Germany.
authors: Martin
authors: M
authors: Bahls
authors: Department of Internal Medicine B (Cardiology), University Medicine Greifswald, Ferdinand-Sauerbruch-Strasse, 17475 Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Greifswald, Germany.
authors: Mathias Christian
authors: MC
authors: Busch
authors: Department of Internal Medicine B (Cardiology), University Medicine Greifswald, Ferdinand-Sauerbruch-Strasse, 17475 Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Greifswald, Germany.
authors: Stephan Burkhard
authors: SB
authors: Felix
mesh_terms: D000075244:Apelin Receptors; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D033081:Shear Strength; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C104575:APLNR protein, human; D000075244:Apelin Receptors; D036341:Intercellular Signaling Peptides and Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D043562:Receptors, G-Protein-Coupled; C495200:apelin-12 peptide; C495199:apelin-13 peptide; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019331:NG-Nitroarginine Methyl Ester
keywords: APJ; Apelin; Endothelial cells; Nitric oxide; Shear stress