Pioglitazone attenuates myocardial ischemia-reperfusion injury via up-regulation of ERK and COX-2
Pioglitazone attenuates myocardial ischemia-reperfusion injury via up-regulation of ERK and COX-2
复制标题
吡格列酮通过上调 ERK 和 COX-2 减轻心肌缺血再灌注损伤
DOI：
10.5582/bst.2012.v6.6.325
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发表时间：
2012-01-01
影响因子：
5.5
通讯作者：
Shen, Lin
中科院分区：
文献类型：
--
作者：
Wang, Hao;Zhu, Qiwei;Shen, Lin
我们以前的研究表明，过氧化物酶体增殖物激活受体(PPAR)γ激动剂吡格列酮(PIO)可能对缺血再灌注损伤具有心脏保护作用；然而，PIO对心肌缺血再灌注(I/R)时p42/p44细胞外信号调节激酶(ERK1/2)和环氧合酶(COX)-2的调节作用尚不清楚。我们确定了PIO是否减少了I/R诱导的心肌细胞凋亡，以及这种保护作用是否源于ERK1/2和COX-2的调节。60只雄性SD大鼠随机分为6组：I/R组；I/R+PIO组(5mg.kg(-1).day(-1))；I/R+PIO(10mg.kg(-1).day(-1))；I/R+PIO(10mg.kg(-1).day(-1))+ERK1/2抑制剂PD98059；I/R+PIO(10mg.kg(-1).day(-1))+GW9662；以及I/R+PD98059。大鼠心肌缺血30min，再灌流120min，取出心脏进行分析。RT-PCR和Western blotting检测ERK1/2和COX-2的表达。PIO组(5和10 mg·kg~(-1)·d~(-1))心肌细胞和NEC数量明显低于I/R组。PIO的心脏保护作用可被PD98059和GW9662取消。与I/R组相比，PIO组ERK1/2和COX-2的磷酸化水平升高。GW9662可逆转PIO诱导的ERK1/2和COX-2的磷酸化。PD98059可逆转PIO诱导的COX-2表达。在大鼠I/R损伤模型中，PIO被证明通过抑制心肌细胞凋亡而起到心脏保护作用。PIO以PPAR-伽马依赖的方式限制梗塞范围。这些结果表明，PIO以COX-2为下游靶点，触发了涉及ERK1/2的MAPK信号通路。
Our previous study demonstrated that the peroxisome proliferator-activated receptor (PPAR) gamma agonist, pioglitazone (PIO), may be cardioprotective against ischemia-reperfusion injury; however, modulation of p42/p44 extracellular signal-regulated kinases (ERK1/2) and cyclooxygenase (COX)-2 by PIO in the myocardium with respect to ischemia-reperfusion (I/R) is only partially understood. We determined if PIO reduces I/R-induced apoptosis in cardiomyocytes, and whether or not this protective effect is due to modulation of ERK1/2 and COX-2. Sixty male Sprague-Dawley rats were randomized and assigned to 1 of 6 groups: I/R; I/R + PIO (5 mg.kg(-1).day(-1)); I/R + PIO (10 mg.kg(-1).day(-1)); I/R + PIO (10 mg.kg(-1).day(-1)) + the ERK1/2 inhibitor, PD98059; I/R + PIO (10 mg.kg(-1).day(-1)) + GW9662; and I/R + PD98059. Rats underwent 30 min of myocardial ischemia and 120 min of reperfusion, and then hearts were harvested for analysis. RT-PCR and Western blotting were performed to detect expression of ERK1/2 and COX-2. The number of TUNEL-positive cardiomyocytes and NEC in the PIO groups (5 and 10 mg.kg(-1).day(-1)) was much lower than the I/R group. The cardioprotective effect of PIO was abrogated by PD98059 and GW9662. Phosphorylation of ERK1/2 and COX-2 was increased in the PIO-treated group compared with the I/R group. GW9662 reversed the expression of ERK1/2 and COX-2 phosphorylation induced by PIO. PD98059 reversed the expression of COX-2 induced by PIO. PIO was shown to be cardioprotective in an I/R injury model in rats via inhibition of cardiomyocyte apoptosis. PIO limited the infarct size in a PPAR-gamma-dependent manner. These results show that PIO triggers the MAPK signaling pathway involving ERK1/2 using COX-2 as the downstream target.