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The Peroxisome Proliferator-Activated Receptor- Agonist Pioglitazone Represses Inflammation in a Peroxisome Proliferator-Activated Receptor-–Dependent Manner In Vitro and In Vivo in Mice

Gabriela Orasanu, MD^_*,, Ouliana Ziouzenkova, PhD^_*,, Pallavi R. Devchand, PhD^_*,, Vedika Nehra, MS^_*,, Osama Hamdy, MD^,, Edward S. Horton, MD^, and Jorge Plutzky, MD^_*,,_*

^_* Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts
Clinical Research Center, Joslin Diabetes Center, Boston, Massachusetts
Harvard Medical School, Boston, Massachusetts

Manuscript received March 10, 2008; revised manuscript received April 22, 2008, accepted April 29, 2008.

^_* Reprint requests and correspondence: Dr. Jorge Plutzky, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, NRB 742, Boston, Massachusetts 02115 (Email: jplutzky{at}rics.bwh.harvard.edu).

Objectives: Our aim was to investigate if the peroxisome proliferator-activated receptor (PPAR)- agonist pioglitazone modulates inflammation through PPAR mechanisms.

Background: The thiazolidinediones (TZDs) pioglitazone and rosiglitazone are insulin-sensitizing PPAR agonists used to treat type 2 diabetes (T2DM). Despite evidence for TZDs limiting inflammation and atherosclerosis, questions exist regarding differential responses to TZDs. In a double-blinded, placebo-controlled 16-week trial among recently diagnosed T2DM subjects (n = 34), pioglitazone-treated subjects manifested lower triglycerides and lacked the increase in soluble vascular cell adhesion molecules (sVCAM)-1 evident in the placebo group. Previously we reported PPAR but not PPAR agonists could repress VCAM-1 expression. Since both triglyceride-lowering and VCAM-1 repression characterize PPAR activation, we studied pioglitazone's effects via PPAR.

Methods: Pioglitazone effects on known PPAR responses—ligand binding domain activation and PPAR target gene expression—were tested in vitro and in vivo, including in wild-type and PPAR-deficient cells and mice, and compared with the effects of other PPAR (rosiglitazone) and PPAR (WY14643) agonists.

Results: Pioglitazone repressed endothelial TNF-induced VCAM-1 messenger ribonucleic acid expression and promoter activity, and induced hepatic IB in a manner dependent on both pioglitazone exposure and PPAR expression. Pioglitazone also activated the PPAR ligand binding domain and induced PPAR target gene expression, with in vitro effects that were most pronounced in endothelial cells. In vivo, pioglitazone administration modulated sVCAM-1 levels and IB expression in wild-type but not PPAR-deficient mice.

Conclusions: Pioglitazone regulates inflammatory target genes in hepatic (IB) and endothelial (VCAM-1) settings in a PPAR-dependent manner. These data offer novel mechanisms that may underlie distinct TZD responses.

Key Words: inflammation • VCAM-1 • PPAR

Abbreviations and Acronyms   ACO = acyl-CoA oxidase   BAEC = bovine aortic endothelial cells   EC = endothelial cell   FPG = fasting plasma glucose   GAPDH = glyceraldehyde-3-phosphate dehydrogenase   HbA1c = hemoglobin A1c   HDL = high-density lipoprotein   HSVEC = human endothelial cells isolated from saphenous vein   LBD = ligand binding domain   LDL = low-density lipoprotein   LPL = lipoprotein lipase   LPS = lipopolysacharide   PPAR = peroxisome proliferator-activated receptor   TG = triglyceride(s)   TNF = tumor necrosis factor   TZD = thiazolidinedione   T2DM = type 2 diabetes mellitus   VCAM = vascular cell adhesion molecule   2h-OGTT = 2-h plasma glucose 200 mg/dl during oral glucose tolerance testing

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