Cyclopentenone prostaglandins (CP-PG), such as prostaglandin A1 (PGA1) or 15-deoxy-12,14-prostaglandin J2 (PGJ2), induce apoptosis in different cell types. PGJ2 is also a potent activator of the peroxisome proliferator-activated receptor- (PPAR). We investigated whether PPAR 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 cellswith a reduced DNA content by CP-PG treatment. EMSA demonstrated an activation of PPAR by PGJ2 and rosiglitazone. Immunohistochemistry of HUVEC and immunoblot analyses of protein extracts showed that PPAR was localized in the nuclei of HUVEC, and that CP-PG treatment decreased the amount of PPAR protein. This degradation was prevented by a pan-caspase inhibitor. Treatment of differentiated, endothelial-like PPAR-deficient stem cells, or of HUVEC transfected with dominant-negative PPAR with CP-PG, induced cell death and apoptosis. Our findings show that PGA1 and PGJ2 induce apoptosis in endothelial cells independent of PPAR. As the synthesis of PGJ2 is increased at sites of inflammation, our results may suggest a possiblemechanism for endothelial damage.