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(Circulation Research. 2001;89:935.)
© 2001 American Heart Association, Inc.

Editorials

The Pleiotropic Nature of the Vascular PPAR Gene Regulatory Pathway

Daniel P. Kelly

From the Center for Cardiovascular Research, Department of Medicine; Departments of Molecular Biology & Pharmacology and Pediatrics, Washington University School of Medicine, St. Louis, Mo.

Correspondence to Daniel P. Kelly, MD, Center for Cardiovascular Research, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8086, St. Louis, MO 63110. E-mail dkelly@imgate.wustl.edu

Key Words: nuclear hormone receptors • vascular smooth muscle • growth factors • atherosclerosis

The peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated transcription factors within the broad nuclear receptor superfamily. Recent evidence indicates that the PPARs play critical regulatory roles in a variety of biologic processes relevant to the heart and vasculature including lipid and energy metabolism, inflammation, and cellular differentiation (reviewed in Desvergne and Wahli¹). The PPAR family includes three members encoded by distinct genes: , ß (also known as or Nuc1), and . The three PPARs are distinguished by tissue- and developmental-specific patterns of expression and by the distinct, albeit overlapping, nature of lipid and eicosanoid ligands capable of activating each receptor. For instance, the expression of PPAR is highly adipose-enriched, whereas PPAR is expressed in tissues with high rates of mitochondrial fatty acid oxidation, such as heart and liver. Ligand activation of PPAR leads to obligate heterodimerization with members of the retinoid X receptor (RXR) subfamily and subsequent binding to cognate DNA response elements within target gene promoter regions. The true endogenous PPAR ligands have not been defined with certainty. Long-chain fatty acids activate each of the PPARs to varying degrees suggesting that lipid species serve as cell-specific PPAR ligands. A number of pharmacologically active, PPAR-specific compounds have been identified leading to a rapidly growing interest in this family of nuclear receptors as targets for drug development. For example, the PPAR activators clofibrate and gemfibrozil have been developed as hypolipidemic agents. Thiazolidinediones (eg, troglitazone, rosiglitazone) are PPAR-specific activators with potent insulin-sensitizing action.

The activity of the PPAR/RXR . . . [Full Text of this Article]

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