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PPAR-Gamma Effects on the Vasculature
  1. Willa A. Hsueh
  1. From the Division of Endocrinology, Diabetes, and Hypertension, University of California at Los Angeles
  1. Address correspondence to: Willa Hsueh, MD, Division of Endocrinology, Diabetes, and Hypertension, University of California-Los Angeles, 900 Veteran Ave, Suite 24-130, Box 957073, Los Angeles, CA 90095

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The peroxisome proliferator activated receptor, PPAR-gamma, is a potential protective factor in vascular injury. This receptor is becoming more important in medicine. Ligands to these receptors are now being administered to diabetic patients, because they function as insulin sensitizers. PPAR comes in three different flavors—alpha, delta, and gamma. This article will focus on gamma. These receptors are classic nuclear receptors, which heterodimerize almost exclusively with RXR-alpha, the retinoic acid X receptor.1 When these receptors partner, they act as transcription factors to regulate gene expression. In the manner typical of steroid hormones such as thyroid hormone, estrogen, and other hormones that bind to nuclear receptors, PPAR-gamma and RXR-alpha can turn on genes by inviting coactivators to bind to DNA, or they can turn off genes by inviting corepressors. In terms of insulin sensitization, there is increasing data that ligands that bind to PPAR-gamma have enhanced insulin-mediated glucose uptake by turning on genes that regulate glucose transport, the identities of which are just beginning to be known.

Polymorphisms of the PPAR-gamma gene have recently been found in patients with Type II diabetes and severe insulin resistance.2 In a group of more than 80 subjects, three were identified with dominant negative mutations in PPAR-gamma, which is associated with a loss of function of that receptor. All three of these patients displayed severe insulin resistance, diabetes, and severe hypertension, usually appearing before the age of 40 years; in each case hypertension preceded the diabetes. These data underscore the importance of PPAR-gamma in diabetes and, unexpectedly, in hypertension, the two of which often occur together. This recognition is consistent with our identification of PPAR-gamma expression in the vasculature.3 We used RNase protection assay to look at the expression of PPAR-gamma messenger RNA in two major cell-types of the vasculature, smooth muscle and …

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