Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:52-57
Published online before print October 31, 2002, doi: 10.1161/01.ATV.0000044461.01844.C9
Published online before print October 31, 2002, doi: 10.1161/01.ATV.0000044461.01844.C9
© 2003 American Heart Association, Inc.
Vascular Biology |
Peroxisome Proliferator-Activated Receptor 
Ligands Increase Release of Nitric Oxide From Endothelial Cells
From the Department of Medicine, Veterans Affairs and Emory University, Medical Centers, Decatur, Ga.
Correspondence to David S. Calnek, PhD, Atlanta VA Medical Center (151P), 1670 Clairmont Rd, Decatur, GA 30033. E-mail dcalnek{at}hotmail.com
Objective— Peroxisome proliferator-activated receptor 
(PPAR) ligands reduce lesion formation in animal models of atherosclerosis by mechanisms that have not been defined completely. We hypothesized that PPAR ligands stimulate endothelial-derived nitric oxide release (·NO) to protect the vascular wall.
Methods and Results— The PPAR ligands, 15-deoxy-
12,14-prostaglandin J2 (15d-PGJ2) or ciglitazone, stimulated a PPAR response element-luciferase reporter construct in transfected porcine pulmonary artery endothelial cells (PAECs), demonstrating that PPAR was transcriptionally functional. Treatment with 15d-PGJ2 or ciglitazone significantly increased release of ·NO from PAECs or human aortic endothelial cells and augmented calcium ionophore–induced ·NO release from human umbilical vein endothelial cells measured by chemiluminescence analysis of culture media. Increases in ·NO release caused by treatment with 15d-PGJ2 occurred at 24 hours, but not after 1 to 16 hours, and were abrogated by treatment with the transcriptional inhibitor 
-amanitin. Overexpression of PPAR or treatment with 9-cis retinoic acid also enhanced PAEC ·NO release. Neither 15d-PGJ2 nor ciglitazone altered eNOS mRNA, whereas 15d-PGJ2, but not ciglitazone, decreased eNOS protein.
Conclusions— Taken together, these findings demonstrate that PPAR ligands stimulate ·NO release from endothelial cells derived from multiple vascular sites, through a transcriptional mechanism unrelated to eNOS expression.
Key Words: peroxisome proliferator-activated receptor • endothelium • nitric oxide • nitric oxide synthase • thiazolidinedione
This article has been cited by other articles:
 |
|
 |
|
  J. M. Kleinhenz, D. J. Kleinhenz, S. You, J. D. Ritzenthaler, J. M. Hansen, D. R. Archer, R. L. Sutliff, and C. M. Hart Disruption of endothelial peroxisome proliferator-activated receptor-{gamma} reduces vascular nitric oxide production Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1647 - H1654. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Potenza, S. Gagliardi, L. De Benedictis, A. Zigrino, E. Tiravanti, G. Colantuono, A. Federici, L. Lorusso, V. Benagiano, M. J. Quon, et al. Treatment of spontaneously hypertensive rats with rosiglitazone ameliorates cardiovascular pathophysiology via antioxidant mechanisms in the vasculature Am J Physiol Endocrinol Metab, September 1, 2009; 297(3): E685 - E694. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. K. Koh, P. C. Oh, and M. J. Quon Does reversal of oxidative stress and inflammation provide vascular protection? Cardiovasc Res, March 1, 2009; 81(4): 649 - 659. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. van Hooland, O. Boey, P. Van der Niepen, C. Van den Branden, and D. Verbeelen Effect of Short-Term Rosiglitazone Therapy in Peritoneal Dialysis Patients Perit. Dial. Int., January 1, 2009; 29(1): 108 - 111. [Full Text] [PDF]
|
|
|
|
|
|
Y. Ye, Y. Lin, S. Manickavasagam, J. R. Perez-Polo, B. C. Tieu, and Y. Birnbaum Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2436 - H2446. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ingbir, I. F. Schwartz, A. Shtabsky, I. Filip, R. Reshef, T. Chernichovski, N. Levin-Iaina, U. Rozovski, Y. Levo, and D. Schwartz Rosiglitazone improves aortic arginine transport, through inhibition of PKC{alpha}, in uremic rats Am J Physiol Renal Physiol, August 1, 2008; 295(2): F471 - F477. [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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 B. K. Chacko, R. T. Chandler, T. L. D'Alessandro, A. Mundhekar, N. K. H. Khoo, N. Botting, S. Barnes, and R. P. Patel Anti-Inflammatory Effects of Isoflavones are Dependent on Flow and Human Endothelial Cell PPAR{gamma} J. Nutr., February 1, 2007; 137(2): 351 - 356. [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]
|
|
|
|
|
|
M. Joner, A. Farb, Q. Cheng, A. V. Finn, E. Acampado, A. P. Burke, K. Skorija, W. Creighton, F. D. Kolodgie, H. K. Gold, et al. Pioglitazone Inhibits In-Stent Restenosis in Atherosclerotic Rabbits by Targeting Transforming Growth Factor-{beta} and MCP-1 Arterioscler Thromb Vasc Biol, January 1, 2007; 27(1): 182 - 189. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A Ajjan and P. J Grant Cardiovascular disease prevention in patients with type 2 diabetes: the role of oral anti-diabetic agents Diabetes and Vascular Disease Research, December 1, 2006; 3(3): 147 - 158. [Abstract] [PDF]
|
|
|
|
 |
|
 H. Boulanger, R. Mansouri, J. F. Gautier, and D. Glotz Are peroxisome proliferator-activated receptors new therapeutic targets in diabetic and non-diabetic nephropathies? Nephrol. Dial. Transplant., October 1, 2006; 21(10): 2696 - 2702. [Full Text] [PDF]
|
|
|
|
|
|
Y. Ye, Y. Lin, S. Atar, M.-H. Huang, J. R. Perez-Polo, B. F. Uretsky, and Y. Birnbaum Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1158 - H1169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M.A.C. Martens, T. J. Rabelink, J. op 't Roodt, E. J.P. de Koning, and F. L.J. Visseren TNF-{alpha} induces endothelial dysfunction in diabetic adults, an effect reversible by the PPAR-{gamma} agonist pioglitazone Eur. Heart J., July 1, 2006; 27(13): 1605 - 1609. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Rocic, B. Rezk, and P. A. Lucchesi PPAR-{gamma} agonists decrease hyperhomcysteinemia and cardiac dysfunction: new hope for ailing diabetic hearts? Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H26 - H28. [Full Text] [PDF]
|
|
|
|
|
|
K. Y. Kim and H. G. Cheon Antiangiogenic Effect of Rosiglitazone Is Mediated via Peroxisome Proliferator-activated Receptor {gamma}-activated Maxi-K Channel Opening in Human Umbilical Vein Endothelial Cells J. Biol. Chem., May 12, 2006; 281(19): 13503 - 13512. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Kendall, C. J. Rubin, P. Mohideen, J.-M. Ledeine, R. Belder, J. Gross, P. Norwood, M. O'Mahony, K. Sall, G. Sloan, et al. Improvement of Glycemic Control, Triglycerides, and HDL Cholesterol Levels With Muraglitazar, a Dual ({alpha}/{gamma}) Peroxisome Proliferator-Activated Receptor Activator, in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy: A double-blind, randomized, pioglitazone-comparative study Diabetes Care, May 1, 2006; 29(5): 1016 - 1023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Campia, L. A. Matuskey, and J. A. Panza Peroxisome Proliferator-Activated Receptor-{gamma} Activation With Pioglitazone Improves Endothelium-Dependent Dilation in Nondiabetic Patients With Major Cardiovascular Risk Factors Circulation, February 14, 2006; 113(6): 867 - 875. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Soumian, R Gibbs, A Davies, and C Albrecht mRNA expression of genes involved in lipid efflux and matrix degradation in occlusive and ectatic atherosclerotic disease J. Clin. Pathol., December 1, 2005; 58(12): 1255 - 1260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hetzel, B. Balletshofer, K. Rittig, D. Walcher, W. Kratzer, V. Hombach, H.-U. Haring, W. Koenig, and N. Marx Rapid Effects of Rosiglitazone Treatment on Endothelial Function and Inflammatory Biomarkers Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1804 - 1809. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Polikandriotis, L. J. Mazzella, H. L. Rupnow, and C. M. Hart Peroxisome Proliferator-Activated Receptor {gamma} Ligands Stimulate Endothelial Nitric Oxide Production Through Distinct Peroxisome Proliferator-Activated Receptor {gamma}-Dependent Mechanisms Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1810 - 1816. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Staels and J.-C. Fruchart Therapeutic Roles of Peroxisome Proliferator-Activated Receptor Agonists Diabetes, August 1, 2005; 54(8): 2460 - 2470. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Khan, S. Riazi, X. Hu, J. Song, J. B. Wade, and C. A. Ecelbarger Regulation of the renal thiazide-sensitive Na-Cl cotransporter, blood pressure, and natriuresis in obese Zucker rats treated with rosiglitazone Am J Physiol Renal Physiol, August 1, 2005; 289(2): F442 - F450. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Kawada, G. Solis, N. Ivey, S. Connors, K. Dennehy, P. Modlinger, R. Hamel, J. T. Kawada, E. Imai, R. Langenbach, et al. Cyclooxygenase-1-Deficient Mice Have High Sleep-to-Wake Blood Pressure Ratios and Renal Vasoconstriction Hypertension, June 1, 2005; 45(6): 1131 - 1138. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Cariou, J.-C. Fruchart, and B. Staels Review: Vascular protective effects of peroxisome proliferator-activated receptor agonists The British Journal of Diabetes & Vascular Disease, May 1, 2005; 5(3): 126 - 132. [Abstract] [PDF]
|
|
|
|
|
|
M. S. Goligorsky Endothelial cell dysfunction: can't live with it, how to live without it Am J Physiol Renal Physiol, May 1, 2005; 288(5): F871 - F880. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Hwang, D. J. Kleinhenz, B. Lassegue, K. K. Griendling, S. Dikalov, and C. M. Hart Peroxisome proliferator-activated receptor-{gamma} ligands regulate endothelial membrane superoxide production Am J Physiol Cell Physiol, April 1, 2005; 288(4): C899 - C905. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Li, K. Chen, N. Sinha, X. Zhang, Y. Wang, A. K. Sinha, F. Romeo, and J. L. Mehta The effects of PPAR-{gamma} ligand pioglitazone on platelet aggregation and arterial thrombus formation Cardiovasc Res, March 1, 2005; 65(4): 907 - 912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Schiffrin Peroxisome proliferator-activated receptors and cardiovascular remodeling Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1037 - H1043. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. R. Moreno and V. Fuster The year in atherothrombosis J. Am. Coll. Cardiol., December 7, 2004; 44(11): 2099 - 2110. [Full Text] [PDF]
|
|
|
|
|
|
S. Wassmann, K. Wassmann, and G. Nickenig Modulation of Oxidant and Antioxidant Enzyme Expression and Function in Vascular Cells Hypertension, October 1, 2004; 44(4): 381 - 386. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Wakino, K. Hayashi, T. Kanda, S. Tatematsu, K. Homma, K. Yoshioka, I. Takamatsu, and T. Saruta Peroxisome Proliferator-Activated Receptor {gamma} Ligands Inhibit Rho/Rho Kinase Pathway by Inducing Protein Tyrosine Phosphatase SHP-2 Circ. Res., September 3, 2004; 95(5): e45 - e55. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Marx, H. Duez, J.-C. Fruchart, and B. Staels Peroxisome Proliferator-Activated Receptors and Atherogenesis: Regulators of Gene Expression in Vascular Cells Circ. Res., May 14, 2004; 94(9): 1168 - 1178. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Verma, M. A. Kuliszewski, S.-H. Li, P. E. Szmitko, L. Zucco, C.-H. Wang, M. V. Badiwala, D. A.G. Mickle, R. D. Weisel, P. W.M. Fedak, et al. C-Reactive Protein Attenuates Endothelial Progenitor Cell Survival, Differentiation, and Function: Further Evidence of a Mechanistic Link Between C-Reactive Protein and Cardiovascular Disease Circulation, May 4, 2004; 109(17): 2058 - 2067. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. F. Watts and B. Staels Regulation of Endothelial Nitric Oxide Synthase by PPAR Agonists: Molecular and Clinical Perspectives Arterioscler Thromb Vasc Biol, April 1, 2004; 24(4): 619 - 621. [Full Text] [PDF]
|
|
|
|
|
|
K. Goya, S. Sumitani, X. Xu, T. Kitamura, H. Yamamoto, S. Kurebayashi, H. Saito, H. Kouhara, S. Kasayama, and I. Kawase Peroxisome Proliferator-Activated Receptor {alpha} Agonists Increase Nitric Oxide Synthase Expression in Vascular Endothelial Cells Arterioscler Thromb Vasc Biol, April 1, 2004; 24(4): 658 - 663. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Wang, N. Ciliberti, S.-H. Li, P. E. Szmitko, R. D. Weisel, P. W.M. Fedak, M. Al-Omran, W.-J. Cherng, R.-K. Li, W. L. Stanford, et al. Rosiglitazone Facilitates Angiogenic Progenitor Cell Differentiation Toward Endothelial Lineage: A New Paradigm in Glitazone Pleiotropy Circulation, March 23, 2004; 109(11): 1392 - 1400. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Ryan, S. P. Didion, S. Mathur, F. M. Faraci, and C. D. Sigmund PPAR{gamma} Agonist Rosiglitazone Improves Vascular Function and Lowers Blood Pressure in Hypertensive Transgenic Mice Hypertension, March 1, 2004; 43(3): 661 - 666. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Song, M. A. Knepper, X. Hu, J. G. Verbalis, and C. A. Ecelbarger Rosiglitazone Activates Renal Sodium- and Water-Reabsorptive Pathways and Lowers Blood Pressure in Normal Rats J. Pharmacol. Exp. Ther., February 1, 2004; 308(2): 426 - 433. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Bagi, A. Koller, and G. Kaley PPAR{gamma} activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H742 - H748. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-H. Cho, Y. J. Choi, S. A. Jo, and I. Jo Nitric Oxide Production and Regulation of Endothelial Nitric-oxide Synthase Phosphorylation by Prolonged Treatment with Troglitazone: EVIDENCE FOR INVOLVEMENT OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) {gamma}-DEPENDENT AND PPAR{gamma}-INDEPENDENT SIGNALING PATHWAYS J. Biol. Chem., January 23, 2004; 279(4): 2499 - 2506. [Abstract] [Full Text] [PDF]
|
|