15-deoxy-delta 12,14-prostaglandin J2 and laminar fluid shear stress stabilize c-IAP1 in vascular endothelial cells.
Laminar shear stress strongly inhibits vascular endothelial cell apoptosis by unknown mechanisms. We reported that shear stress stimulates endothelial cells to produce 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) by elevating the expression level of lipocalin-type prostaglandin D synthase. To investigate the role of 15d-PGJ2 produced in the vascular wall, we examined the effect of 15d-PGJ2 on endothelial cell apoptosis. We induced apoptosis in human umbilical vein endothelial cells (HUVECs) by growth factor deprivation. 15d-PGJ2 strongly inhibited DNA ladder formation, nuclear fragmentation, and caspase-3-like activity in HUVECs. To elucidate the mechanism by which 15d-PGJ2 inhibits endothelial cell apoptosis, we examined expression of the inhibitor of apoptosis proteins (IAP) cellular-IAP1 (c-IAP1), c-IAP2, x-linked IAP, and survivin in HUVECs. In parallel with the inhibition of apoptosis, 15d-PGJ2 elevated the expression level of c-IAP1 protein in a dose- and time-dependent manner without changing the mRNA level. Laminar shear stress also induced c-IAP1 expression. Chase experiments with the use of cycloheximide revealed that 15d-PGJ2 and shear stress both inhibited the proteolytic degradation of c-IAP1 protein. These results suggested that 15d-PGJ2 inhibits endothelial cell apoptosis through, at least in part, c-IAP1 protein stabilization. This mechanism might be involved in the antiapoptotic effect of laminar shear stress.
Taba
Yoji
Y
Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
Miyagi
Megumi
M
Miwa
Yoshikazu
Y
Inoue
Hiroyasu
H
Takahashi-Yanaga
Fumi
F
Morimoto
Sachio
S
Sasaguri
Toshiyuki
T
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007155:Immunologic Factors / Q000378:metabolism / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors; D054834:Lipocalins; D008156:Luciferases / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D009363:Neoplasm Proteins; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000096:biosynthesis* / Q000494:pharmacology*; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013314:Stress, Mechanical; D000077022:Survivin; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D000077288:Troglitazone; D044767:Ubiquitin-Protein Ligases; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects
C097240:15-deoxy-delta(12,14)-prostaglandin J2; C107489:BIRC5 protein, human; D002839:Chromans; D007004:Hypoglycemic Agents; D007155:Immunologic Factors; D051034:Inhibitor of Apoptosis Proteins; D054834:Lipocalins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011500:Protein Synthesis Inhibitors; D011506:Proteins; D012333:RNA, Messenger; D000077022:Survivin; D013844:Thiazoles; D045162:Thiazolidinediones; D004247:DNA; D003513:Cycloheximide; D008156:Luciferases; C494833:BIRC2 protein, human; D044767:Ubiquitin-Protein Ligases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D000077288:Troglitazone; D015230:Prostaglandin D2