This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 25/9/1810    most recent 01.ATV.0000177805.65864.d4v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Polikandriotis, J. A. Articles by Hart, C. M. Search for Related Content PubMed PubMed Citation Articles by Polikandriotis, J. A. Articles by Hart, C. M. Related Collections Endothelium/vascular type/nitric oxide

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1810.)
© 2005 American Heart Association, Inc.

Vascular Biology

Peroxisome Proliferator-Activated Receptor Ligands Stimulate Endothelial Nitric Oxide Production Through Distinct Peroxisome Proliferator-Activated Receptor –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 (PPAR) ligands 15-deoxy-^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-ligand–stimulated increases in endothelial cell NO production.

Methods and Results— Treating human umbilical vein endothelial cells (HUVEC) with PPAR 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 ligands and with the PPAR antagonist GW9662 (2 µmol/L), which fully inhibited stimulation of a luciferase reporter gene, or with small interfering RNA to PPAR, which reduced HUVEC PPAR expression. Treatment with either small interfering RNA to PPAR 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-stimulated endothelial cell NO release and emphasize that individual ligands exert their effects through distinct PPAR-dependent mechanisms.

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

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

This article has been cited by other articles:

				H. Adachi, Y. Takemoto, T. Bungo, and T. Ohkubo Chicken leptin receptor is functional in activating JAK-STATpathway in vitro J. Endocrinol., May 1, 2008; 197(2): 335 - 342. [Abstract] [Full Text] [PDF]

				J. G. Boyle, P. J. Logan, M.-A. Ewart, J. A. Reihill, S. A. Ritchie, J. M. C. Connell, S. J. Cleland, and I. P. Salt Rosiglitazone Stimulates Nitric Oxide Synthesis in Human Aortic Endothelial Cells via AMP-activated Protein Kinase J. Biol. Chem., April 25, 2008; 283(17): 11210 - 11217. [Abstract] [Full Text] [PDF]

				F. Scalera, J. Martens-Lobenhoffer, A. Bukowska, U. Lendeckel, M. Tager, and S. M. Bode-Boger Effect of Telmisartan on Nitric Oxide-Asymmetrical Dimethylarginine System: Role of Angiotensin II Type 1 Receptor and Peroxisome Proliferator Activated Receptor {gamma} Signaling During Endothelial Aging Hypertension, March 1, 2008; 51(3): 696 - 703. [Abstract] [Full Text] [PDF]

				S. Z. Duan, M. G. Usher, and R. M. Mortensen Peroxisome Proliferator-Activated Receptor-{gamma}-Mediated Effects in the Vasculature Circ. Res., February 15, 2008; 102(3): 283 - 294. [Abstract] [Full Text] [PDF]

				P. E. Westerweel, K. den Ouden, T. Q. Nguyen, R. Goldschmeding, J. A. Joles, and M. C. Verhaar Amelioration of anti-Thy1-glomerulonephritis by PPAR-{gamma} agonism without increase of endothelial progenitor cell homing Am J Physiol Renal Physiol, February 1, 2008; 294(2): F379 - F384. [Abstract] [Full Text] [PDF]

				F. Desjardins, B. Sekkali, W. Verreth, M. Pelat, D. De Keyzer, A. Mertens, G. Smith, M.-C. Herregods, P. Holvoet, and J.-L. Balligand Rosuvastatin increases vascular endothelial PPAR{gamma} expression and corrects blood pressure variability in obese dyslipidaemic mice Eur. Heart J., January 1, 2008; 29(1): 128 - 137. [Abstract] [Full Text] [PDF]

				M. H. Napimoga, S. M. Vieira, D. Dal-Secco, A. Freitas, F. O. Souto, F. L. Mestriner, J. C. Alves-Filho, R. Grespan, T. Kawai, S. H. Ferreira, et al. Peroxisome Proliferator-Activated Receptor-{gamma} Ligand, 15-Deoxy-{Delta}12,14-Prostaglandin J2, Reduces Neutrophil Migration via a Nitric Oxide Pathway J. Immunol., January 1, 2008; 180(1): 609 - 617. [Abstract] [Full Text] [PDF]

				J. Li, A. Wilson, R. Kuruba, Q. Zhang, X. Gao, F. He, L.-M. Zhang, B. R. Pitt, W. Xie, and S. Li FXR-mediated regulation of eNOS expression in vascular endothelial cells Cardiovasc Res, January 1, 2008; 77(1): 169 - 177. [Abstract] [Full Text] [PDF]

				G. Ceolotto, A. Gallo, I. Papparella, L. Franco, E. Murphy, E. Iori, E. Pagnin, G. P. Fadini, M. Albiero, A. Semplicini, et al. Rosiglitazone Reduces Glucose-Induced Oxidative Stress Mediated by NAD(P)H Oxidase via AMPK-Dependent Mechanism Arterioscler. Thromb. Vasc. Biol., December 1, 2007; 27(12): 2627 - 2633. [Abstract] [Full Text] [PDF]

				K. M. Hong, J. A. Belperio, M. P. Keane, M. D. Burdick, and R. M. Strieter Differentiation of Human Circulating Fibrocytes as Mediated by Transforming Growth Factor-beta and Peroxisome Proliferator-activated Receptor {gamma} J. Biol. Chem., August 3, 2007; 282(31): 22910 - 22920. [Abstract] [Full Text] [PDF]

				D. M. Dudzinski and T. Michel Life history of eNOS: Partners and pathways Cardiovasc Res, July 15, 2007; 75(2): 247 - 260. [Abstract] [Full Text] [PDF]

				S. A. Sorrentino, F. H. Bahlmann, C. Besler, M. Muller, S. Schulz, N. Kirchhoff, C. Doerries, T. Horvath, A. Limbourg, F. Limbourg, et al. Oxidant Stress Impairs In Vivo Reendothelialization Capacity of Endothelial Progenitor Cells From Patients With Type 2 Diabetes Mellitus: Restoration by the Peroxisome Proliferator-Activated Receptor-{gamma} Agonist Rosiglitazone Circulation, July 10, 2007; 116(2): 163 - 173. [Abstract] [Full Text] [PDF]

				N. Toda, K. Ayajiki, and T. Okamura Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation Pharmacol. Rev., March 1, 2007; 59(1): 54 - 87. [Abstract] [Full Text] [PDF]

				A. Ptasinska, S. Wang, J. Zhang, R. A. Wesley, and R. L. Danner Nitric oxide activation of peroxisome proliferator-activated receptor gamma through a p38 MAPK signaling pathway FASEB J, March 1, 2007; 21(3): 950 - 961. [Abstract] [Full Text] [PDF]

				J. D. Brown and J. Plutzky Peroxisome Proliferator Activated Receptors as Transcriptional Nodal Points and Therapeutic Targets Circulation, January 30, 2007; 115(4): 518 - 533. [Abstract] [Full Text] [PDF]

				A. Alfranca, M. A. Iniguez, M. Fresno, and J. M. Redondo Prostanoid signal transduction and gene expression in the endothelium: Role in cardiovascular diseases Cardiovasc Res, June 1, 2006; 70(3): 446 - 456. [Abstract] [Full Text] [PDF]