The myocardial infarct size-limiting effect of sitagliptin is PKA-dependent, whereas the protective effect of pioglitazone is partially dependent on PKA
The myocardial infarct size-limiting effect of sitagliptin is PKA-dependent, whereas the protective effect of pioglitazone is partially dependent on PKA
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DOI：
10.1152/ajpheart.00867.2009
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发表时间：
2010-05-01
影响因子：
4.8
通讯作者：
Birnbaum, Yochai
中科院分区：
文献类型：
--
作者：
Ye, Yumei;Keyes, Kyle T.;Birnbaum, Yochai
叶Y，凯斯KT，张C，佩雷斯-波罗JR，林Y，伯恩鲍姆Y。西格列汀的心肌梗死范围限制作用是PKA依赖性的，而吡格列酮的保护作用部分依赖于PKA。Am J Physiol Heart Circ Physiol 298：H1454-H1465，2010.首次发表于2010年3月5日; doi：10.1152/ajpheart. 00867.2009.-吡格列酮（PIO）和胰高血糖素样肽-1（GLP-1）类似物限制实验模型中的梗死面积（IS）。二肽基肽酶- IV抑制剂（可增加GLP-1的内源性水平）对心肌保护的作用尚不清楚。我们研究了西格列汀（SIT）和PIO是否对小鼠的IS限制具有累加效应。小鼠接受3天或14天口服SIT（300 mg.kg（-1）.day（-1））、PIO（5 mg. kg（-1）.day（-1））、SIT + PIO或溶媒。此外，小鼠在缺血前1小时接受静脉内H-89 [20 mg/kg，蛋白激酶A（PKA）抑制剂]或溶媒。大鼠心肌缺血30 min，再灌注4 h。与对照组（46.2 +/- 2.8%）相比，SIT、PIO和SIT + PIO 3天显著降低了IS（24.3 +/- 2.7、23.0 +/- 0.8和14.7 +/- 0.9%）。H-89可完全阻断SIT的作用，部分阻断PIO的作用。SIT，而不是PIO，增加cAMP水平。PKA活性增加PIO和在更大程度上由SIT。PIO，而不是SIT，增加胞浆磷脂酶A（2）和环氧合酶-2活性。因此，6-酮- PGF（1 α）和15-脱氧-PGJ（2）通过PIO而不是SIT增加。相比之下，SIT和较小程度的PIO增加了15-epi-lipoxin A（4）水平。H-89完全阻断SIT和PIO对15-epi-lipoxin A（4）水平的影响。PIO，并在更大程度上SIT，增加内皮型一氧化氮合酶和cAMP反应元件结合蛋白磷酸化，H-89阻断的效果。在14天的预处理实验中，对照组IS为46.4 +/- 1.0%，SIT为16.9 +/- 0.6%（P < 0.001），PIO为19.1 +/- 1.1%（P = 0.014），SIT + PIO为12.9 +/- 0.7%（P < 0.001）。我们发现SIT和PIO通过不同的途径限制IS。SIT的保护作用是通过cAMP依赖性PKA激活，而PIO通过PKA依赖性和非依赖性途径介导其作用。
Ye Y, Keyes KT, Zhang C, Perez-Polo JR, Lin Y, Birnbaum Y. The myocardial infarct size-limiting effect of sitagliptin is PKA-dependent, whereas the protective effect of pioglitazone is partially dependent on PKA. Am J Physiol Heart Circ Physiol 298: H1454-H1465, 2010. First published March 5, 2010; doi: 10.1152/ajpheart. 00867.2009.-Pioglitazone (PIO) and glucagon-like peptide-1 (GLP-1) analogs limit infarct size (IS) in experimental models. The effects of the dipeptidylpeptidase- IV inhibitors, which increase the endogenous levels of GLP-1, on myocardial protection, are unknown. We studied whether sitagliptin (SIT) and PIO have additive effects on IS limitation in the mouse. Mice received 3-day or 14-day oral SIT (300 mg.kg(-1).day(-1)), PIO (5 mg.kg(-1).day(-1)), SIT + PIO, or vehicle. In addition, mice received intravenous H-89 [20 mg/kg, a protein kinase A (PKA) inhibitor] or vehicle 1 h before ischemia. Rats underwent 30 min myocardial ischemia and 4 h reperfusion. SIT, PIO, and SIT + PIO for 3 days significantly reduced IS (24.3 +/- 2.7, 23.0 +/- 0.8, and 14.7 +/- 0.9%) compared with controls (46.2 +/- 2.8%). H-89 completely blocked the effect of SIT and partially blocked the PIO effect. SIT, but not PIO, increased cAMP levels. PKA activity was increased by PIO and to a greater extent by SIT. PIO, but not SIT, increased cytosolic phospholipase A(2) and cyclooxygenase-2 activity. Accordingly, 6-ke-to- PGF(1 alpha) and 15-deoxy-PGJ(2) increased by PIO but not SIT. In contrast, SIT, and to a lesser extent PIO, increased 15-epi-lipoxin A(4) levels. H-89 completely blocked the effect of SIT and PIO on 15-epi-lipoxin A(4) levels. PIO, and to a greater extent SIT, increased endothelial nitric oxide synthase and cAMP response element-binding protein phosphorylation, an effect that was blocked by H-89. With a 14-day pretreatment experiment, IS was 46.4 +/- 1.0% in the control group, 16.9 +/- 0.6% in SIT (P < 0.001), 19.1 +/- 1.1% in PIO (P = 0.014), and 12.9 +/- 0.7% in SIT + PIO (P < 0.001). We found that SIT and PIO limit IS using different pathways. The protective effect of SIT is via cAMP-dependent PKA activation, whereas PIO mediates its effects via both PKA-dependent and -independent pathways.