John S. Dunn Chair in Cardiology Research and Education, Department of Medicine, Section of Cardiology, Baylor College of Medicine, 1709 Dryden Road, Houston, TX 77030, USA.
Am J Physiol Heart Circ Physiol. 2010 May;298(5):H1454-65. doi: 10.1152/ajpheart.00867.2009. Epub 2010 Mar 5.
Pioglitazone (PIO) and glucagon-like peptide-1 (GLP-1) analogs limit infarct size (IS) in experimental models. The effects of the dipeptidyl-peptidase-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-keto-PGF(1alpha) 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.
吡格列酮（PIO）和胰高血糖素样肽-1（GLP-1）类似物可限制实验模型中的梗死面积（IS）。二肽基肽酶-4 抑制剂可增加内源性 GLP-1 水平，但其对心肌保护的影响尚不清楚。我们研究了二肽基肽酶-4 抑制剂西他列汀（SIT）和 PIO 是否对小鼠的 IS 限制具有相加作用。小鼠接受 3 天或 14 天的口服 SIT（300mg.kg（-1）.day（-1））、PIO（5mg.kg（-1）.day（-1））、SIT+PIO 或载体。此外，在缺血前 1 小时，小鼠还接受静脉注射 H-89[20mg/kg，蛋白激酶 A（PKA）抑制剂]或载体。大鼠经历 30 分钟心肌缺血和 4 小时再灌注。与对照组（46.2+/-2.8%）相比，SIT、PIO 和 SIT+PIO 治疗 3 天可显著降低 IS（24.3+/-2.7%、23.0+/-0.8%和 14.7+/-0.9%）。H-89 完全阻断 SIT 的作用，并部分阻断 PIO 的作用。SIT 可增加 cAMP 水平，但 PIO 不能。PKA 活性被 PIO 增强，并被 SIT 增强到更大程度。PIO 可增加细胞溶质磷脂酶 A（2）和环加氧酶-2 活性，但 SIT 不能。因此，6-酮-PGF（1alpha）和 15-脱氧-PGJ（2）由 PIO 增加，但不是 SIT。相反，SIT 可增加 15-epi-脂氧素 A（4）水平，但 PIO 不能。与 SIT 相比，H-89 完全阻断了 PIO 对 15-epi-脂氧素 A（4）水平的作用。PIO 可增强内皮型一氧化氮合酶和 cAMP 反应元件结合蛋白磷酸化，这种作用被 H-89 阻断。在 14 天的预处理实验中，对照组的 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 激活来实现的，而 PIO 通过 PKA 依赖性和非依赖性途径来介导其作用。
