Cyclopentenone prostaglandins (CP-PG), such as
prostaglandin A1 (
PGA1) or
15-deoxy-Delta(12,14)-prostaglandin J2 (
PGJ2), induce apoptosis in different cell types.
PGJ2 is also a potent activator of the
peroxisome proliferator-activated receptor-gamma (
PPARgamma). We investigated whether
PPARgamma regulates CP-PG-induced apoptosis in endothelial cells (EC). We show that CP-PG induce apoptosis in human umbilical vein EC (HUVEC). Incubation with
PGA1 or
PGJ2 for 24 h reduced HUVEC number and viability, while the synthetic activators Wy14643 or
rosiglitazone had no effect. Flow cytometry and cell cycle analysis revealed externalized
phosphatidylserine,
caspase-3 activation, and an increased percentage of cells with a reduced
DNA content by CP-PG treatment. EMSA demonstrated an activation of
PPARgamma by
PGJ2 and
rosiglitazone. Immunohistochemistry of HUVEC and immunoblot analyses of
protein extracts showed that
PPARgamma was localized in the nuclei of HUVEC, and that CP-PG treatment decreased the amount of
PPARgamma protein. This degradation was prevented by a pan-
caspase inhibitor. Treatment of differentiated, endothelial-like
PPARgamma-deficient stem cells, or of HUVEC transfected with dominant-negative
PPARgamma with CP-PG, induced cell death and apoptosis. Our findings show that
PGA1 and
PGJ2 induce apoptosis in endothelial cells independent of
PPARgamma. As the synthesis of
PGJ2 is increased at sites of
inflammation, our results may suggest a possible mechanism for endothelial damage.