Anandamide induces apoptosis in human endothelial cells: its regulation system and clinical implications.
Anandamide (AEA), an endogenous cannabinoid, is generated by macrophages during shock conditions, and is thought to be a causative mediator of septic shock. Thus, we hypothesized that AEA plays a crucial role in endothelial cell (EC) injury. Here, we demonstrate that AEA induces apoptosis in a time-and dose-dependent manner in human umbilical vein endothelial cells (HUVECs). AEA triggered phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and p38 mitogen activated protein kinase. AEA also showed a marked increase of interleukin Ibeta- converting enzyme (ICE)CED-3 family protease (caspase-3) activity. AEA-induced EC death was inhibited by a selective vanilloid receptor 1 (VR1) antagonist, capsazepine, and was enhanced by a VR1 agonist, capsaicin, indicating that AEA induces apoptosis in ECs via VR1. In conclusion, we propose that AEA may play a crucial role in EC injury under conditions of shock, and that the use of inhibitors of the AEA regulation system may have a therapeutic effect under these conditions.
Department of Laboratory and Molecular Medicine, Faculty of Medicine, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan.
Kazuyo
K
Yamaji
Krishna Pada
KP
Sarker
Koichi
K
Kawahara
Satoshi
S
Iino
Munekazu
M
Yamakuchi
Kazuhiro
K
Abeyama
Teruto
T
Hashiguchi
Ikuro
I
Maruyama
D017209:Apoptosis / Q000187:drug effects*; D001095:Arachidonic Acids / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D063388:Endocannabinoids; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D053284:Polyunsaturated Alkamides; D011955:Receptors, Drug / Q000502:physiology; D012772:Shock, Septic / Q000473:pathology; D014471:Umbilical Veins / Q000166:cytology; D048051:p38 Mitogen-Activated Protein Kinases
D001095:Arachidonic Acids; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D011955:Receptors, Drug; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C078814:anandamide