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Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1810-1816
Published online before print July 14, 2005, doi: 10.1161/01.ATV.0000177805.65864.d4
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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1810.)
© 2005 American Heart Association, Inc.

Vascular Biology

Peroxisome Proliferator-Activated Receptor {gamma} Ligands Stimulate Endothelial Nitric Oxide Production Through Distinct Peroxisome Proliferator-Activated Receptor {gamma}–Dependent Mechanisms

John A. Polikandriotis; Louis J. Mazzella; Heidi L. Rupnow; C. Michael Hart

From the Department of Medicine, Atlanta Veterans Affairs and Emory University Medical Centers, Atlanta, Ga.

Correspondence to John A. Polikandriotis, PhD, Atlanta VAMC (151-P), 1670 Clairmont Rd, Decatur, GA 30033. E-mail jpolika{at}emory.edu

Objective— We recently reported that the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) ligands 15-deoxy-{Delta}12,14-prostaglandin J2 (15d-PGJ2) and ciglitazone increased cultured endothelial cell nitric oxide (NO) release without increasing the expression of endothelial nitric oxide synthase (eNOS). The current study was designed to characterize further the molecular mechanisms underlying PPAR{gamma}-ligand–stimulated increases in endothelial cell NO production.

Methods and Results— Treating human umbilical vein endothelial cells (HUVEC) with PPAR{gamma} ligands (10 µmol/L 15d-PGJ2, ciglitazone, or rosiglitazone) for 24 hours increased NOS activity and NO release. In selected studies, HUVEC were treated with PPAR{gamma} ligands and with the PPAR{gamma} antagonist GW9662 (2 µmol/L), which fully inhibited stimulation of a luciferase reporter gene, or with small interfering RNA to PPAR{gamma}, which reduced HUVEC PPAR{gamma} expression. Treatment with either small interfering RNA to PPAR{gamma} or GW9662 inhibited 15d-PGJ2-, ciglitazone-, and rosiglitazone-induced increases in endothelial cell NO release. Rosiglitazone and 15d-PGJ2, but not ciglitazone, increased heat shock protein 90-eNOS interaction and eNOS ser1177 phosphorylation. The heat shock protein 90 inhibitor geldanamycin attenuated 15d-PGJ2- and rosiglitazone-stimulated NOS activity and NO production.

Conclusions— These findings further clarify mechanisms involved in PPAR{gamma}-stimulated endothelial cell NO release and emphasize that individual ligands exert their effects through distinct PPAR{gamma}-dependent mechanisms.

This study characterizes the molecular mechanisms underlying peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) ligand–stimulated increases in endothelial nitric oxide production. The data indicate that different PPAR{gamma} ligands increase endothelial cell nitric oxide production by distinct PPAR{gamma}-dependent signaling pathways that could represent novel targets for pharmacological intervention in vascular disease.


Key Words: peroxisome proliferator-activated receptor {gamma} • nitric oxide • endothelium • endothelial nitric oxide synthase • thiazolidinedione




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