Pioglitazone limits myocardial infarct size, activates Akt, and upregulates cPLA2 and COX-2 in a PPAR-γ-independent manner
Pioglitazone limits myocardial infarct size, activates Akt, and upregulates cPLA2 and COX-2 in a PPAR-γ-independent manner
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DOI：
10.1007/s00395-011-0162-3
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发表时间：
2011-05-01
影响因子：
9.5
通讯作者：
Ye, Yumei
中科院分区：
文献类型：
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作者：
Birnbaum, Yochai;Long, Bo;Ye, Yumei
吡格列酮（PIO）是一种PPAR-γ激动剂，通过激活Akt和上调胞浆磷脂酶A（2）（cPLA（2））和环氧合酶（考克斯）-2来限制心肌梗死范围。然而，PIO具有几种PPAR-gamma独立效应。我们评估了PIO是否限制了PPAR-gamma敲除小鼠的心肌梗死范围，减轻了缺氧-复氧损伤，上调了PPAR-gamma敲除心肌细胞中P-Akt、cPLA（2）和考克斯-2的表达。通过将α MHC-Cre小鼠与PPAR-gamma（loxp/loxp）小鼠杂交产生心脏特异性诱导型PPAR-gamma敲除小鼠。在腹膜内给予他莫昔芬（20 mg/kg/天）7天后实现了PPAR-gamma缺失。小鼠接受PIO（10 mg/kg/天）或载体3天，并经历冠状动脉闭塞（30 min），随后再灌注（4 h）。我们用蓝色染料评估危险区，用TTC评估梗死面积。培养的成年心肌细胞的PPAR-gamma（loxp/loxp/cre）小鼠没有或与他莫昔芬预处理与或没有PIO孵育，并进行2小时缺氧/2小时复氧。心脏特异性PPAR-gamma敲除显著增加梗死面积。PIO使PPAR-gamma基因敲除小鼠的梗死面积减少了51%，使PPAR-gamma基因完整小鼠的梗死面积减少了55%。删除PPAR-gamma基因会增加体外细胞死亡。PIO减少具有和不具有完整PPAR-gamma的细胞中的细胞死亡。在有和没有完整PPAR-gamma的细胞中，缺氧/复氧后，PIO同样增加心肌Ser-473 P-Akt、cPLA（2）和考克斯-2水平。PIO以不依赖于PPAR-gamma的方式限制小鼠的梗死面积。PIO激活Akt，增加cPLA（2）和考克斯-2的表达，保护成年心肌细胞免受缺氧/复氧的影响，而不依赖于PPAR-gamma的激活。
Pioglitazone (PIO), a PPAR-gamma agonist, limits myocardial infarct size by activating Akt and upregulating cytosolic phospholipase A(2) (cPLA(2)) and cyclooxygenase (COX)-2. However, PIO has several PPAR-gamma-independent effects. We assessed whether PIO limits myocardial infarct size in PPAR-gamma-knockout mice, attenuates hypoxia-reoxygenation injury and upregulates P-Akt, cPLA(2), and COX-2 expression in PPAR-gamma-knockout cardiomyocytes. Cardiac-specific inducible PPAR-gamma knockout mice were generated by crossing alpha MHC-Cre mice to PPAR-gamma(loxp/loxp) mice. PPAR-gamma deletion was achieved after 7 days of intraperitoneal tamoxifen (20 mg/kg/day) administration. Mice received PIO (10 mg/kg/day), or vehicle, for 3 days and underwent coronary occlusion (30 min) followed by reperfusion (4 h). We assessed the area at risk by blue dye and infarct size by TTC. Cultured adult cardiomyocytes of PPAR-gamma(loxp/loxp/cre) mice without or with pretreatment with tamoxifen were incubated with or without PIO and subjected to 2 h hypoxia/2 h reoxygenation. Cardiac-specific PPAR-gamma knockout significantly increased infarct size. PIO reduced infarct size by 51% in PPAR-gamma knockout mice and by 55% in mice with intact PPAR-gamma. Deleting the PPAR-gamma gene increased cell death in vitro. PIO reduced cell death in cells with and without intact PPAR-gamma. PIO similarly increased myocardial Ser-473 P-Akt, cPLA(2), and COX-2 levels after hypoxia/reoxygenation in cells with and without intact PPAR-gamma. PIO limited infarct size in mice in a PPAR-gamma-independent manner. PIO activated Akt, increased the expression of cPLA(2) and COX-2, and protected adult cardiomyocytes against the effects of hypoxia/reoxygenation independent of PPAR-gamma activation.