Activation of Signal Transducer and Activator of Transcription-3 by a Peroxisome Proliferator-Activated Receptor Gamma Agonist Contributes to Neuroprotection in the Peri-Infarct Region After Ischemia in Oophorectomized Rats
Activation of Signal Transducer and Activator of Transcription-3 by a Peroxisome Proliferator-Activated Receptor Gamma Agonist Contributes to Neuroprotection in the Peri-Infarct Region After Ischemia in Oophorectomized Rats
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DOI：
10.1161/strokeaha.111.618926
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发表时间：
2012-02-01
期刊：
影响因子：
8.3
通讯作者：
Nagahiro, Shinji
中科院分区：
文献类型：
--
作者：
Kinouchi, Tomoya;Kitazato, Keiko T.;Nagahiro, Shinji
背景和目的：过氧化体增殖物激活受体-γ(PPAR-γ)激动剂吡格列酮(PGZ)对脑缺血后磷酸化信号转导和转录激活因子-3(p-STAT3)的作用仍存在争议。雌激素是否通过雌激素受体α介导p-STAT3的增加也不清楚。方法：雌性Wistar大鼠在大脑中动脉阻断再灌注90min前2天、1天、1小时分别注射1.0或2.5 mg/kg的前列腺素Z，并与空白对照组比较。结果：去卵巢大鼠脑皮质梗塞面积较未去卵巢大鼠大，经去卵巢大鼠皮质梗塞面积缩小。随着梗塞面积的缩小，与赋形剂对照组相比，注射PGZ的大鼠脑梗死区PPAR-γ和p-STAT3增加，而雌激素受体α增加。PPAR-γ和p-STAT3的增加与该区域抗凋亡和生存基因的反式激活以及caspase-3的减少有关。PPAR-γ或STAT3的抑制剂可阻断PGZ诱导的神经保护和p-STAT3的升高。更重要的是，PGZ增加的p-STAT3与PPAR-γ结合，复合体移位到核内，通过p-STAT3与反应元件对接。结论：PGZ在脑梗塞周围区激活p-STAT3和PPAR-γ对脑缺血后的神经保护是必要的，即使在绝经后的卒中患者，PGZ也可能是有益的。(笔划。2012；43：478-483。)
Background and Purpose-The role of the phosphorylated signal transducer and activator of transcription-3 (p-STAT3) after cerebral ischemia by the peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist pioglitazone (PGZ) remains controversial. Whether the increase in p-STAT3 by estrogen is mediated by the estrogen receptor alpha is also obscure. We examined the role of p-STAT3, PPAR gamma, and estrogen receptor alpha against ischemic brain damage after PGZ treatment.Methods-Female Wistar rats subjected or not subjected to bilateral oophorectomy were injected with 1.0 or 2.5 mg/kg PGZ 2 days, 1 day, and 1 hour before 90-minute middle cerebral artery occlusion-reperfusion and compared with vehicle-control rats.Results-The cortical infarct size was larger in ovariectomized than in nonovarietomized rats; it was reduced by PGZ treatment. Inversely with the reduction of the infarct size, PPAR gamma, and p-STAT3 but not estrogen receptor alpha in the pen-infarct area were increased in PGZ-treated compared with vehicle-control rats. The increase in PPAR gamma and p-STAT3 was associated with the transactivation of antiapoptotic and survival genes and the reduction of caspase-3 in this area. Inhibitors of PPAR gamma or STAT3 abolished the PGZ-induced neuroprotection and the increase in p-STAT3. More importantly, p-STAT3 increased by PGZ was bound to PPAR gamma and the complex translocated to the nucleus to dock to the response element through p-STAT3.Conclusions-Our findings suggest that the activation in the pen-infarct region of p-STAT3 and PPAR gamma by PGZ is essential for neuroprotection after ischemia and that PGZ may be of benefit even in postmenopausal stroke patients. (Stroke. 2012;43:478-483.)