This Article Full Text Full Text (PDF) 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 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 Brown, J. D. Articles by Plutzky, J. Search for Related Content PubMed Articles by Brown, J. D. Articles by Plutzky, J. Related Collections Lipid and lipoprotein metabolism Type 2 diabetes Mechanism of atherosclerosis/growth factors Other Vascular biology Pathophysiology Gene expression Gene regulation

(Circulation. 2007;115:518-533.)
© 2007 American Heart Association, Inc.

Basic Science for Clinicians

Peroxisome Proliferator–Activated Receptors as Transcriptional Nodal Points and Therapeutic Targets

Jonathan D. Brown, MD; Jorge Plutzky, MD

From the Cardiovascular Division, Brigham and Women’s Hospital, Boston, Mass.

Correspondence to Jorge Plutzky, MD, 77 Ave Louis Pasteur, NRB 742, Boston, MA 02115. E-mail jplutzky{at}rics.bwh.harvard.edu

Peroxisome proliferator–activated receptors (PPARs) are ligand-activated transcription factors involved in the transcriptional regulation of key metabolic pathways such as lipid metabolism, adipogenesis, and insulin sensitivity. More recent work implicates all 3 PPAR isotypes (, , and , also known as ß or ß/) in inflammatory and atherosclerotic pathways. Because these nuclear receptors are activated by extracellular signals and control multiple gene targets, PPARs can be seen as nodes that control multiple inputs and outputs involved in energy balance, providing insight into how metabolism and the vasculature may be integrated. The ongoing clinical use of fibrates, which activate PPAR, and thiazolidinediones, which activate PPAR, establishes these receptors as viable drug targets, whereas considerable in vitro animal model and human surrogate marker studies suggest that PPAR activation may limit inflammation and atherosclerosis. Together, these various observations have stimulated intense interest in PPARs as therapeutic targets and led to large-scale cardiovascular end-point trials with PPAR agonists. The first of these studies has generated mixed results that require careful review, especially in anticipation of additional clinical trial data and ongoing attempts to develop novel PPAR modulators. Such analysis of the existing PPAR data, the appropriate use of currently approved PPAR agonists, and continued progress in PPAR therapeutics will be predicated on a better understanding of PPAR biology.

Key Words: atherosclerosis • diabetes mellitus • inflammation • metabolism • lipoproteins • peroxisome proliferator-activated receptors • transcription

This article has been cited by other articles:

				G. Orasanu, O. Ziouzenkova, P. R. Devchand, V. Nehra, O. Hamdy, E. S. Horton, and J. Plutzky The Peroxisome Proliferator-Activated Receptor-{gamma} Agonist Pioglitazone Represses Inflammation in a Peroxisome Proliferator-Activated Receptor-{alpha}-Dependent Manner In Vitro and In Vivo in Mice J. Am. Coll. Cardiol., July 2, 2008; (2008) j.jacc.2008.04.055v1. [Abstract] [Full Text] [PDF]

				S. Paruchuri, Y. Jiang, C. Feng, S. A. Francis, J. Plutzky, and J. A. Boyce Leukotriene E4 Activates Peroxisome Proliferator-activated Receptor {gamma} and Induces Prostaglandin D2 Generation by Human Mast Cells J. Biol. Chem., June 13, 2008; 283(24): 16477 - 16487. [Abstract] [Full Text] [PDF]

				C. M. Werner and M. Bohm Review: The therapeutic role of RAS blockade in chronic heart failure Therapeutic Advances in Cardiovascular Disease, June 1, 2008; 2(3): 167 - 177. [Abstract] [PDF]

				K. Wang and Y.-J. Y. Wan Nuclear Receptors and Inflammatory Diseases Experimental Biology and Medicine, May 1, 2008; 233(5): 496 - 506. [Abstract] [Full Text] [PDF]

				K. Fujita, N. Maeda, M. Sonoda, K. Ohashi, T. Hibuse, H. Nishizawa, M. Nishida, A. Hiuge, A. Kurata, S. Kihara, et al. Adiponectin Protects Against Angiotensin II-Induced Cardiac Fibrosis Through Activation of PPAR-{alpha} Arterioscler. Thromb. Vasc. Biol., May 1, 2008; 28(5): 863 - 870. [Abstract] [Full Text] [PDF]

				S. Kourimate, C. Le May, C. Langhi, A. L. Jarnoux, K. Ouguerram, Y. Zair, P. Nguyen, M. Krempf, B. Cariou, and P. Costet Dual Mechanisms for the Fibrate-mediated Repression of Proprotein Convertase Subtilisin/Kexin Type 9 J. Biol. Chem., April 11, 2008; 283(15): 9666 - 9673. [Abstract] [Full Text] [PDF]

				Y. H. Kim and H. J. Han High-Glucose-Induced Prostaglandin E2 and Peroxisome Proliferator-Activated Receptor {delta} Promote Mouse Embryonic Stem Cell Proliferation Stem Cells, March 1, 2008; 26(3): 745 - 755. [Abstract] [Full Text] [PDF]

				S. H. Ramirez, D. Heilman, B. Morsey, R. Potula, J. Haorah, and Y. Persidsky Activation of Peroxisome Proliferator-Activated Receptor {gamma} (PPAR{gamma}) Suppresses Rho GTPases in Human Brain Microvascular Endothelial Cells and Inhibits Adhesion and Transendothelial Migration of HIV-1 Infected Monocytes J. Immunol., February 1, 2008; 180(3): 1854 - 1865. [Abstract] [Full Text] [PDF]

				T. Kanda, S. Wakino, K. Hayashi, and J. Plutzky Cardiovascular Disease, Chronic Kidney Disease, and Type 2 Diabetes Mellitus: Proceeding with Caution at a Dangerous Intersection J. Am. Soc. Nephrol., January 1, 2008; 19(1): 4 - 7. [Full Text] [PDF]

				L. Ravaux, C. Denoyelle, C. Monne, I. Limon, M. Raymondjean, and K. El Hadri Inhibition of Interleukin-1{beta}-Induced Group IIA Secretory Phospholipase A2 Expression by Peroxisome Proliferator-Activated Receptors (PPARs) in Rat Vascular Smooth Muscle Cells: Cooperation between PPAR{beta} and the Proto-Oncogene BCL-6 Mol. Cell. Biol., December 1, 2007; 27(23): 8374 - 8387. [Abstract] [Full Text] [PDF]

				P. J. Bajwa, A. Alioua, J. W. Lee, D. S. Straus, L. Toro, and C. Lytle Fenofibrate inhibits intestinal Cl secretion by blocking basolateral KCNQ1 K+ channels Am J Physiol Gastrointest Liver Physiol, December 1, 2007; 293(6): G1288 - G1299. [Abstract] [Full Text] [PDF]

				J. Li, Y. Doerffel, B. Hocher, and T. Unger Inflammation in the genesis of hypertension and its complications the role of angiotensin II Nephrol. Dial. Transplant., November 1, 2007; 22(11): 3107 - 3109. [Full Text] [PDF]

				C. Yagil and Y. Yagil Peroxisome Proliferator-Activated Receptor {alpha}: Friend or Foe? Hypertension, November 1, 2007; 50(5): 847 - 850. [Full Text] [PDF]

				D. H. Solomon and W. C. Winkelmayer Cardiovascular Risk and the Thiazolidinediones: Deja Vu All Over Again? JAMA, September 12, 2007; 298(10): 1216 - 1218. [Full Text] [PDF]

				D. F. Reilly, E. J. Westgate, and G. A. FitzGerald Peripheral Circadian Clocks in the Vasculature Arterioscler. Thromb. Vasc. Biol., August 1, 2007; 27(8): 1694 - 1705. [Abstract] [Full Text] [PDF]

				A. Pozzi, M. R. Ibanez, A. E. Gatica, S. Yang, S. Wei, S. Mei, J. R. Falck, and J. H. Capdevila Peroxisomal Proliferator-activated Receptor-{alpha}-dependent Inhibition of Endothelial Cell Proliferation and Tumorigenesis J. Biol. Chem., June 15, 2007; 282(24): 17685 - 17695. [Abstract] [Full Text] [PDF]

				F. Chang, L. A Jaber, H. D Berlie, and M. B. O'Connell Evolution of Peroxisome Proliferator-Activated Receptor Agonists Ann. Pharmacother., June 1, 2007; 41(6): 973 - 983. [Abstract] [Full Text] [PDF]