The peroxisome proliferator-activated receptor-gamma agonist pioglitazone represses inflammation in a peroxisome proliferator-activated receptor-alpha-dependent manner in vitro and in vivo in mice.
The peroxisome proliferator-activated receptor-gamma agonist pioglitazone represses inflammation in a peroxisome proliferator-activated receptor-alpha-dependent manner in vitro and in vivo in mice.
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DOI：
10.1016/j.jacc.2008.04.055
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发表时间：
2008-09-02
影响因子：
24
通讯作者：
Plutzky, Jorge
中科院分区：
文献类型：
--
作者：
Orasanu, Gabriela;Ziouzenkova, Ouliana;Devchand, Pallavi R.;Nehra, Vedika;Hamdy, Osama;Horton, Edward S.;Plutzky, Jorge
研究PPARγ激动剂吡格列酮是否通过PPARα机制调节炎症。噻唑烷二酮类（TZD）、吡格列酮和罗格列酮是用于治疗2型糖尿病（T2 DM）的胰岛素增敏性PPARγ激动剂。尽管有证据表明TZD限制炎症和动脉粥样硬化，但关于TZD的差异反应存在问题。在最近诊断的T2 DM受试者（n=34）中进行的一项双盲、安慰剂对照16周试验中，吡格列酮治疗的受试者表现出甘油三酯（TG）降低，并且缺乏安慰剂组中明显的可溶性VCAM-1（sVCAM-1）增加。以前我们报道过PPARα激动剂能抑制VCAM-1的表达，但未报道过PPARγ激动剂。由于TG降低和VCAM-1抑制都是PPARα激活的特征，因此我们研究了吡格列酮通过PPARα的作用。在体外和体内（包括野生型和PPARα缺陷细胞和小鼠）检测了吡格列酮对已知的PPARα反应（配体结合域（LBD）激活和PPARα靶基因表达）的影响，并与其他PPARγ（罗格列酮）和PPARα（WY 14643）激动剂进行了比较。吡格列酮抑制内皮TNFα诱导的VCAM-1 mRNA表达和启动子活性，并以依赖于吡格列酮暴露和PPARα表达的方式诱导肝IκBα。吡格列酮还激活了PPARα LBD并诱导了PPARα靶基因表达，体外效应在内皮细胞中最为明显。在体内，吡格列酮给药可调节野生型小鼠sVCAM-1水平和IκBα表达，但对PPARα缺陷小鼠无影响。吡格列酮以PPARα依赖性方式调节肝脏（IκBα）和内皮（VCAM-1）环境中的炎症靶基因。这些数据提供了新的机制，可能是不同的TZD反应的基础。
To investigate if the PPARγ 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 manifest lower triglycerides (TG) and lacked the increase in soluble VCAM-1 (sVCAM-1) evident in the placebo group. Previously we reported PPARα but not PPARγ agonists could repress VCAM-1 expression. Since both TG-lowering and VCAM-1 repression characterize PPARα activation, we studied pioglitazone’s effects via PPARα. Pioglitazone effects on known PPARα responses - ligand binding domain (LBD) activation and PPARα target gene expression - were tested in vitro and in vivo, including in wildtype and PPARα-deficient cells and mice, and compared to other PPARγ (rosiglitazone) and PPARα (WY14643) agonists. Pioglitazone repressed endothelial TNFα-induced VCAM-1 mRNA expression and promoter activity, and induced hepatic IκBα in a manner dependent on both pioglitazone exposure and PPARα expression. Pioglitazone also activated the PPARα LBD 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 wildtype but not PPARα-deficient mice. Pioglitazone regulates inflammatory target genes in hepatic (IκBα) and endothelial (VCAM-1) settings in a PPARα-dependent manner. This data offers novel mechanisms that may underlie distinct TZD responses.
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影响因子：
20.1
作者：
Ahmed, W;Orasanu, G;Plutzky, J
通讯作者：
Plutzky, J
影响因子：
168.9
作者：
Dormandy, JA;Charbonnel, B;Taton, J
通讯作者：
Taton, J
影响因子：
16
作者：
Ghisletti, Serena;Huang, Wendy;Glass, Christopher K.
通讯作者：
Glass, Christopher K.
影响因子：
5.9
作者：
Dandona, P;Aljada, A;Chaudhuri, A
通讯作者：
Chaudhuri, A
影响因子：
3.2
作者：
Gao, J;Garulacan, LA;Dambach, DM
通讯作者：
Dambach, DM