title: Cyclic AMP alleviates endoplasmic stress and programmed cell death induced by lipopolysaccharides in human endothelial cells.
abstract: The possible protection provided by enhancement of the cAMP signal in the process of lipopolysaccharide (LPS)-induced endothelial cell death has been addressed, with special emphasis on the endoplasmic initiation of caspase-12-mediated apoptosis. Human umbilical vein endothelial cells were challenged with LPS to reduce viability after 12 h to less than 20% that of the control. Cell death was preceded by ultrastructural disintegration at the endoplasmic reticulum, PERK-phosphorylation, degradation of caspase-12-like protein and cleavage of caspase 9, resulting in apoptosis through the activation of caspase 3. Treatment with a cell-permeable cAMP analogue led to a dose-dependent reduction of cell death over time, mitigated endoplasmic reticulum disturbances, reduced phosphorylation of PERK, and the degradation of caspases 12, 9 and 3. The selective inhibition of caspase 9 completely supplanted the anti-apoptotic effects obtained by cAMP, while being without any influence on caspase 12 degradation. The data suggest that cAMP positively modulates early endoplasmic alterations and caspase activation in LPS-induced apoptosis.
authors.affiliation: Surgical Research Division, University Clinic of Surgery, Bonn, Germany.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Schildberg
authors.forename: Susanne
authors.initials: S
authors.lastname: Schulz
authors.forename: Frank
authors.initials: F
authors.lastname: Dombrowski
authors.forename: Thomas
authors.initials: T
authors.lastname: Minor
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D013312:Stress, Physiological / Q000188:drug therapy*; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D008070:Lipopolysaccharides; D000242:Cyclic AMP; D020169:Caspases