Cyclic AMP alleviates endoplasmic stress and programmed cell death induced by lipopolysaccharides in human endothelial cells.
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.
Schildberg
Frank A
FA
Surgical Research Division, University Clinic of Surgery, Bonn, Germany.
Schulz
Susanne
S
Dombrowski
Frank
F
Minor
Thomas
T
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
D008070:Lipopolysaccharides; D000242:Cyclic AMP; D020169:Caspases