title: Statins inhibit hypoxia-induced endothelial proliferation by preventing calcium-induced ROS formation.
abstract: Pathological hypoxia plays an important role in many diseases, such as atherosclerosis, cancer, and rheumatoid arthritis. The aim of the present study was to examine the effects of different statins on hypoxia-induced endothelial cell signalling. Human umbilical cord vein endothelial cells (HUVEC) were treated with NaCN (CN, 2.5 mmol/l) to simulate a transient hypoxia. The CN-induced increase of endothelial cell numbers was significantly (n = 10, p < 0.01) reduced by the Ca(2+) chelator BAPTA (10 micromol/l), or the reactive oxygen species (ROS) scavenger N-acetylcysteine (ACC, 1 mmol/l), or the NAD(P)H-oxidase inhibitor diphenyleneiodonium (DPI, 5 micromol/l). In detail, cell numbers were (in percentage of control): 163.24 (CN), 90.06 (CN+ACC), 92.06 (CN+DPI). Intracellular-Ca(2+) and -ROS, analysed by fluorescence imaging, were significantly increased by CN. Interestingly, the CN-induced increase of ROS was in part Ca(2+)-dependent, whereas the Ca(2+) increase was not ROS-dependent. Simvastatin (5 micromol/l), fluvastatin (2.5 micromol/l), and cerivastatin (0.1 micromol/l) all reduced CN-induced proliferation, ROS generation and Ca(2+) increase. Cell viability was not reduced by the statins and the antiproliferative effect was completely reversed by mevalonate (500 micromol/l). In conclusion our study demonstrates that statins block hypoxia-associated endothelial proliferation by preventing the increase of Ca(2+) and ROS.
authors.affiliation: Department of Cardiology and Angiology, Justus-Liebig-University of Giessen, Klinikstr. 36, 35392 Giessen, Germany.
authors.forename: Christian Alexander
authors.initials: CA
authors.lastname: Schaefer
authors.forename: Christoph Ruediger Wolfram
authors.initials: CR
authors.lastname: Kuhlmann
authors.forename: Sebastian
authors.initials: S
authors.lastname: Weiterer
authors.forename: Annett
authors.initials: A
authors.lastname: Fehsecke
authors.forename: Yaser
authors.initials: Y
authors.lastname: Abdallah
authors.forename: Claudia
authors.initials: C
authors.lastname: Schaefer
authors.forename: Martina Barbara
authors.initials: MB
authors.lastname: Schaefer
authors.forename: Konstantin
authors.initials: K
authors.lastname: Mayer
authors.forename: Harald
authors.initials: H
authors.lastname: Tillmanns
authors.forename: Ali
authors.initials: A
authors.lastname: Erdogan
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009861:Onium Compounds / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012966:Sodium Cyanide / Q000494:pharmacology
chemical_list: D002614:Chelating Agents; D016166:Free Radical Scavengers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009861:Onium Compounds; D017382:Reactive Oxygen Species; D004533:Egtazic Acid; C007517:diphenyleneiodonium; D019001:Nitric Oxide Synthase; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D012966:Sodium Cyanide; D002118:Calcium; D000111:Acetylcysteine