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

• Published in: Journal of the American College of Cardiology Vol. 52; no. 10; pp. 869 - 881
• Main Authors: Orasanu, Gabriela, Ziouzenkova, Ouliana, Devchand, Pallavi R., Nehra, Vedika, Hamdy, Osama, Horton, Edward S., Plutzky, Jorge
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.09.2008
• Subjects: Animals; Cardiovascular; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - physiopathology; Double-Blind Method; Endothelins - drug effects; Female; Humans; Hypoglycemic Agents - therapeutic use; In Vitro Techniques; inflammation; Inflammation - drug therapy; Internal Medicine; Male; Mice; Middle Aged; Pioglitazone; PPAR; PPAR alpha - agonists; PPAR gamma - agonists; Rosiglitazone; Thiazolidinediones - therapeutic use; Tumor Necrosis Factor-alpha - drug effects; Vascular Cell Adhesion Molecule-1 - drug effects; VCAM-1; T2DM; 2h-OGTT; BAEC; LPL; ACO; TNF; LPS; LBD; HDL; VCAM; VCAM-1; TG; PPAR; HSVEC; inflammation; LDL; FPG; GAPDH; HbA1c; EC; TZD; high-density lipoprotein; acyl-CoA oxidase; triglyceride(s); 2-h plasma glucose ≥200 mg/dl during oral glucose tolerance testing; type 2 diabetes mellitus; human endothelial cells isolated from saphenous vein; glyceraldehyde-3-phosphate dehydrogenase; peroxisome proliferator-activated receptor; hemoglobin A 1c; thiazolidinedione; endothelial cell; low-density lipoprotein; lipopolysacharide; HbA 1c; tumor necrosis factor; lipoprotein lipase; bovine aortic endothelial cells; vascular cell adhesion molecule; fasting plasma glucose; ligand binding domain
• ISSN: 0735-1097; 1558-3597; 1558-3597
• DOI: 10.1016/j.jacc.2008.04.055

The Peroxisome Proliferator-Activated Receptor-γ Agonist Pioglitazone Represses Inflammation in a Peroxisome Proliferator-Activated Receptor-α–Dependent Manner In Vitro and In Vivo in Mice Gabriela Orasanu, Ouliana Ziouzenkova, Pallavi R. Devchand, Vedika Nehra, Osama Hamdy, Edward S. Horton, Jorge Plutzky The peroxisome proliferator-activated receptor (PPAR)-γ-activating thiazolidinediones (TZDs) pioglitazone and rosiglitazone are insulin sensitizers that limit inflammation and decrease atherosclerosis. Recent data, however, have raised questions regarding distinct TZD effects. In a randomized, placebo-controlled clinical study among patients with recently diagnosed type 2 diabetes, pioglitazone exerted effects consistent with PPARα activation. In studying pioglitazone effects on PPARα responses, including in PPARα-deficient experimental settings in vitro and in vivo, we found that pioglitazone exerted known PPARα effects in vitro but not in the absence of PPARα, including regulation of endothelial vascular cell adhesion molecule-1 and hepatic IκBα expression. Pioglitazone modulated these same targets in vivo but not in PPARα-deficient mice. Our aim was to investigate if the peroxisome proliferator-activated receptor (PPAR)-γ agonist pioglitazone modulates inflammation through PPARα mechanisms. The thiazolidinediones (TZDs) pioglitazone and rosiglitazone are insulin-sensitizing PPARγ 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 PPARα but not PPARγ agonists could repress VCAM-1 expression. Since both triglyceride-lowering and VCAM-1 repression characterize PPARα activation, we studied pioglitazone's effects via PPARα. Pioglitazone effects on known PPARα responses—ligand binding domain activation and PPARα target gene expression—were tested in vitro and in vivo, including in wild-type and PPARα-deficient cells and mice, and compared with the effects of other PPARγ (rosiglitazone) and PPARα (WY14643) agonists. Pioglitazone repressed endothelial TNFα-induced VCAM-1 messenger ribonucleic acid expression and promoter activity, and induced hepatic IκBα in a manner dependent on both pioglitazone exposure and PPARα expression. Pioglitazone also activated the PPARα ligand binding domain and induced PPARα target gene expression, with in vitro effects that were most pronounced in endothelial cells. In vivo, pioglitazone administration modulated sVCAM-1 levels and IκBα expression in wild-type but not PPARα-deficient mice. Pioglitazone regulates inflammatory target genes in hepatic (IκBα) and endothelial (VCAM-1) settings in a PPARα-dependent manner. These data offer novel mechanisms that may underlie distinct TZD responses.