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15-Deoxy-^12,14-prostaglandin J₂ and laminar fluid shear stress stabilize c-IAP1 in vascular endothelial cells

¹Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582; ²Third Department of Internal Medicine, University of the Ryukyus School of Medicine, Okinawa 903-0215; ³Department of Pharmacology, National Cardiovascular Center Research Institute, Osaha 565-8565, Japan

Submitted 2 December 2002 ; accepted in final form 27 February 2003

Laminar shear stress strongly inhibits vascular endothelial cell apoptosis by unknown mechanisms. We reported that shear stress stimulates endothelial cells to produce 15-deoxy-^12,14-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.

apoptosis; troglitazone; peroxisome proliferator-activated receptor-

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