doi: 10.1161/01.ATV.0000127311.38703.1f
© 2004 American Heart Association, Inc.
Editorials |
PPAR-
Agonists: Shifting Attention from the Belly to the Heart?
From the Department of Vascular Medicine (J.P.H.v.W.), University Medical Center Utrecht, and the Department of Nephrology and Hypertension (T.J.R.), University Medical Center Leiden, The Netherlands
Correspondence to Prof T. J. Rabelink, MD, PhD, University Medical Center Leiden, Department of Nephrology and Hypertension, Room C3-P, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail t.rabelink@lumc.nl
An extract of the first 250 words of the full text is provided, because this article has no abstract. |
Second generation thiazolidinediones (TZDs), synthetic ligands for the peroxisome proliferator activated receptor-
(PPAR-), have recently been introduced in clinical medicine to improve insulin resistance in type 2 diabetes. The two isoforms of PPAR- are preferentially expressed in adipose tissue, and the improvement of insulin resistance in skeletal muscle and liver tissue is probably secondary to enhanced lipid storage in subcutaneous adipocytes and improved adipocyte function, as reflected by the altered secretion of adipocytokines.1 These effects are mediated by receptor-dependent activation of the PPAR-–retinoid X receptor (RXR) complex and subsequent transcriptional activation of target genes.1 The PPAR-1 isoform is also expressed in endothelial cells, vascular smooth muscle cells (VSMCs), and monocytes/macrophages in the vasculature.2,3 PPAR- agonists have been shown to have interesting effects on these cells, which appear to be partially independent of the PPAR-–RXR–mediated transcriptional effects.4 For example, in endothelial cells, TZDs have been shown to enhance endothelial nitric oxide synthase (eNOS) activity by phosphorylation and to inhibit leukocyte–endothelial cell interaction.5,6 TZDs inhibit growth factor–induced proliferation and migration of VSMCs.7 Also in vivo, in a model of angiotensin II induced hypertension, TZDs could normalize endothelial function and correct structural vascular abnormalities.8 In monocytes/macrophages, TZDs upregulate the scavenger receptor CD369 and induce the cholesterol efflux pomp ATP-binding cassette, subfamily A, member 1 (ABCA1), suggesting altered lipid handling by macrophages whereby proatherogenic lipoproteins are taken up and antiatherogenic lipoproteins are generated.10 Finally, and perhaps most importantly, TZDs are very potent inhibitors of inflammation. There appears to be a
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