title: High glucose-induced apoptosis through store-operated calcium entry and calcineurin in human umbilical vein endothelial cells.
abstract: Diabetes mellitus causes multiple cardiovascular complications. Previous studies have shown that prolonged exposure (96 h) of human umbilical vein endothelial cells (HUVECs) to hyperglycemia causes a significant increase in apoptosis. We report here that this increase in apoptosis is associated with an increase in Ca(2+) current (whole cell patch-clamp recorded) resulting from Ca(2+) entry mediated by store-operated channels (SOCs). The number of apoptotic cells after prolonged high glucose (HG, 30 mmol/L) exposure was significantly reduced in the presence of the SOC inhibitor 2-APB or of La(3+). A marked increase (approximately 80%) in Ca(2+)-dependent calcineurin (CN-A) phosphatase activity also occurred after prolonged HG exposure. Prolonged HG exposure-induced increase in CN-A activity was prevented by 2-APB, and selective CN-A phosphatase inhibition by FK506 or calmodulin inhibition by calmidazolium decreased HG-induced apoptosis. Blocking hydrogen peroxide production using catalase or inhibiting the tyrosine kinase pp60(src) during prolonged exposure to HG, resulted in a marked decrease in apoptosis and was further associated with a significant reduction in CN-A phosphatase activity. The results demonstrate a significant role for Ca(2+) entry in HG-induced apoptosis in HUVECs, and suggest that this role is mediated via H(2)O(2) generation and the action of the Ca(2+)-activated protein phosphatase calcineurin.
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8078, Université Paris XI, Hôpital Marie Lannelongue, 92350 Le Plessis Robinson, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Tamareille
authors.forename: Olivier
authors.initials: O
authors.lastname: Mignen
authors.forename: Thierry
authors.initials: T
authors.lastname: Capiod
authors.forename: Catherine
authors.initials: C
authors.lastname: Rücker-Martin
authors.forename: Danielle
authors.initials: D
authors.lastname: Feuvray
mesh_terms: D017209:Apoptosis; D001896:Boron Compounds / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002374:Catalase / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors; D016559:Tacrolimus / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D001896:Boron Compounds; D015220:Calcium Channels; D002147:Calmodulin; D007093:Imidazoles; C031938:calmidazolium; D006861:Hydrogen Peroxide; C109986:2-aminoethoxydiphenyl borate; D002374:Catalase; D016392:Proto-Oncogene Proteins pp60(c-src); C120817:calcineurin phosphatase; D019703:Calcineurin; D010744:Phosphoric Monoester Hydrolases; D005947:Glucose; D002118:Calcium; D016559:Tacrolimus