Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Apoptosis / drug effects
-
Blotting, Western
-
Caspase 3
-
Caspases / metabolism
-
Cell Nucleus / metabolism
-
Cell Nucleus / ultrastructure
-
Cells, Cultured
-
Chromans / pharmacology
-
Cycloheximide / pharmacology
-
DNA / biosynthesis
-
DNA / genetics
-
Dose-Response Relationship, Drug
-
Electrophoresis, Polyacrylamide Gel
-
Endothelium, Vascular / cytology
-
Endothelium, Vascular / drug effects
-
Endothelium, Vascular / metabolism*
-
Humans
-
Hypoglycemic Agents / pharmacology
-
Immunologic Factors / metabolism
-
Immunologic Factors / pharmacology*
-
Inhibitor of Apoptosis Proteins
-
Intramolecular Oxidoreductases / antagonists & inhibitors
-
Lipocalins
-
Luciferases / genetics
-
Microtubule-Associated Proteins / biosynthesis
-
Neoplasm Proteins
-
Prostaglandin D2 / analogs & derivatives
-
Prostaglandin D2 / biosynthesis*
-
Prostaglandin D2 / pharmacology*
-
Protein Biosynthesis
-
Protein Synthesis Inhibitors / pharmacology
-
Proteins / metabolism*
-
RNA, Messenger / biosynthesis
-
Reverse Transcriptase Polymerase Chain Reaction
-
Stress, Mechanical*
-
Survivin
-
Thiazoles / pharmacology
-
Thiazolidinediones*
-
Troglitazone
-
Ubiquitin-Protein Ligases
-
Umbilical Veins / cytology
-
Umbilical Veins / drug effects
Substances
-
15-deoxy-delta(12,14)-prostaglandin J2
-
BIRC5 protein, human
-
Chromans
-
Hypoglycemic Agents
-
Immunologic Factors
-
Inhibitor of Apoptosis Proteins
-
Lipocalins
-
Microtubule-Associated Proteins
-
Neoplasm Proteins
-
Protein Synthesis Inhibitors
-
Proteins
-
RNA, Messenger
-
Survivin
-
Thiazoles
-
Thiazolidinediones
-
DNA
-
Cycloheximide
-
Luciferases
-
BIRC2 protein, human
-
Ubiquitin-Protein Ligases
-
CASP3 protein, human
-
Caspase 3
-
Caspases
-
Intramolecular Oxidoreductases
-
prostaglandin R2 D-isomerase
-
Troglitazone
-
Prostaglandin D2