on January 29, 2004
Published online before print January 29, 2004, doi: 10.1161/01.ATV.0000118682.58708.78
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on August 29, 2003
Accepted on January 8, 2004
Peroxisome Proliferator-Activated Receptor 
Agonists Increase Nitric Oxide Synthase Expression in Vascular Endothelial Cells
Kayoko Goya ;
From the Department of Molecular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
* To whom correspondence should be addressed. E-mail: kasayama{at}imed3.med.osaka-u.ac.jp.
Objective--There has been accumulating evidence demonstrating that activators for peroxisome proliferator-activated receptor 
(PPAR) have antiinflammatory, antiatherogenic, and vasodilatory effects. We hypothesized that PPAR activators can modulate endothelial nitric oxide synthase (eNOS) expression and its activity in cultured vascular endothelial cells.
Methods and Results-- Bovine aortic endothelial cells were treated with the PPAR activator fenofibrate. The amount of eNOS activity and the expression of eNOS protein and its mRNA were determined. Our data show that treatment with fenofibrate for 48 hours resulted in an increase in eNOS activity. Fenofibrate failed to increase eNOS activity within 1 hour. Fenofibrate also increased eNOS protein as well as its mRNA levels. RU486, which has been shown to antagonize PPAR action, inhibited the fenofibrate-induced upregulation of eNOS protein expression. WY14643 and bezafibrate also increased eNOS protein levels, whereas rosiglitazone did not. Transient transfection experiments using human eNOS promoter construct showed that fenofibrate failed to enhance eNOS promoter activity. Actinomycin D studies demonstrated that the half-life of eNOS mRNA increased with fenofibrate treatment.
Conclusions-- PPAR activators upregulate eNOS expression, mainly through mechanisms of stabilizing eNOS mRNA. This is a new observation to explain one of the mechanisms of PPAR-mediated cardiovascular protection.
Key words: atherosclerosis • endothelium • nitric oxide • vascular biology • vasodilatation
This article has been cited by other articles:
 |
|
 |
|
  J. Blanco-Rivero, I. Marquez-Rodas, F. E. Xavier, R. Aras-Lopez, I. Arroyo-Villa, M. Ferrer, and G. Balfagon Long-term fenofibrate treatment impairs endothelium-dependent dilation to acetylcholine by altering the cyclooxygenase pathway Cardiovasc Res, July 15, 2007; 75(2): 398 - 407. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Yakubu, R. H. Nsaif, and A. O. Oyekan Peroxisome Proliferator-Activated Receptor {alpha} Activation-Mediated Regulation of Endothelin-1 Production via Nitric Oxide and Protein Kinase C Signaling Pathways in Piglet Cerebral Microvascular Endothelial Cell Culture J. Pharmacol. Exp. Ther., February 1, 2007; 320(2): 774 - 781. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Formoso, H. Chen, J.-a Kim, M. Montagnani, A. Consoli, and M. J. Quon Dehydroepiandrosterone Mimics Acute Actions of Insulin to Stimulate Production of Both Nitric Oxide and Endothelin 1 via Distinct Phosphatidylinositol 3-Kinase- and Mitogen-Activated Protein Kinase-Dependent Pathways in Vascular Endothelium Mol. Endocrinol., May 1, 2006; 20(5): 1153 - 1163. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. K. Koh, M. J. Quon, S. H. Han, W.-J. Chung, J. Y. Ahn, J.-a Kim, Y. Lee, and E. K. Shin Additive Beneficial Effects of Fenofibrate Combined With Candesartan in the Treatment of Hypertriglyceridemic Hypertensive Patients Diabetes Care, February 1, 2006; 29(2): 195 - 201. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Han, M. J. Quon, and K. K. Koh Beneficial Vascular and Metabolic Effects of Peroxisome Proliferator-Activated Receptor-{alpha} Activators Hypertension, November 1, 2005; 46(5): 1086 - 1092. [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]
|
|
|
|
 |
|
 K. K. Koh, M. J. Quon, S. H. Han, W.-J. Chung, J. Y. Ahn, Y.-H. Seo, I. S. Choi, and E. K. Shin Additive Beneficial Effects of Fenofibrate Combined With Atorvastatin in the Treatment of Combined Hyperlipidemia J. Am. Coll. Cardiol., May 17, 2005; 45(10): 1649 - 1653. [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]
|
|
|
|
|
|
G. T. McMahon, J. Plutzky, E. Daher, T. Bhattacharyya, G. Grunberger, and M. F. DiCarli Effect of a Peroxisome Proliferator-Activated Receptor-{gamma} Agonist on Myocardial Blood Flow in Type 2 Diabetes Diabetes Care, May 1, 2005; 28(5): 1145 - 1150. [Abstract] [Full Text] [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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|