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194 THE PROLIFERATOR-ACTIVATED RECEPTOR GAMMA LIGAND ROSIGLITAZONE STIMULATES ENDOTHELIAL NITRIC OXIDE PRODUCTION BY INCREASING ENDOTHELIAL NITRIC OXIDE SYNTHASE PHOSPHORYLATION AND INTERACTIONS WITH HEAT SHOCK PROTEIN 90
  1. J. A. Polikandriots,
  2. H. L. Rupnow,
  3. C. M. Hart
  1. Atlanta, GA.

Abstract

Purpose The antidiabetic thiazolidinedione medications activate the peroxisome proliferator-activated receptor gamma (PPARγ) and exert vascular protective effects through incompletely defined mechanisms. We recently reported that the PPARγ ligands 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and ciglitizone increased cultured endothelial cell (EC) nitric oxide (NO) release without increasing the expression of endothelial nitric oxide synthase (eNOS).

Methods To further characterize the molecular mechanisms underlying PPARγ ligand-stimulated increases in EC NO production, human umbilical vein endothelial cells (HUVEC) were treated with 10 μM rosiglitazone for 24 hours followed by analysis of NO production, eNOS and heat shock protein 90 (hsp90) activation.

Results Rosiglitazone increased EC NO release without altering eNOS or hsp90 expression. However, rosiglitazone increased hsp90-eNOS protein-protein interactions. The hsp90 antagonist geldanamycin attenuated rosiglitazone-induced increases in NO production as well as eNOS-hsp90 association. Rosiglitazone also increased the phosphorylation of eNOS at ser1177.

Conclusions These findings demonstrate that the PPARγ ligand rosiglitazone stimulates EC NO release by mechanisms involving eNOS-protein interactions and alterations in eNOS phosphorylation. These findings provide further insight into mechanisms of thiazolidinedione-induced vascular protection.

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