*L'Université Nantes Angers Le Mans; †Université d'Angers, Laboratoire Cardioprotection, Remodelage et Thrombose; ‡CHU Angers, Laboratoire d'Hématologie; §Université d'Angers, INSERM U771, CNRS UMR 6214, CHU Angers, Département de Biochimie et Génétique; and ∥CHU Angers, Service de Cardiologie, Angers, France.
Shock. 2014 Feb;41(2):166-71. doi: 10.1097/SHK.0000000000000072.
Acute myocardial infarction is a leading cause of mortality and morbidity worldwide. Although essential for successful recovery, myocardium reperfusion is associated with reperfusion injury. Two major cell survival signaling cascades are known to be protective against ischemia-reperfusion (I/R) injury: the reperfusion injury salvage kinase, including Akt, extracellular signal-regulated kinase 1/2, and the downstream target GSK-3β, and the survivor activating factor enhancement, which involves STAT-3. Pharmacologic inhibition of factor Xa has been shown to attenuate I/R injury, but the cellular mechanism is poorly understood. Our aim was to determine the role of whole blood in fondaparinux (FDX)-induced cardioprotection and the involvement of reperfusion injury salvage kinase and survivor activating factor enhancement pathways. We investigated FDX ability to prevent in vivo I/R injury using a transient coronary ligation rat model and ex vivo using a model of crystalloid-perfused isolated rat heart. In both models, infarct size was assessed after 120 min of reperfusion. Myocardial tissues were collected after 15 and 30 min of reperfusion for Western blot analysis. In vivo, FDX decreased infarct size by 29% and induced significant STAT-3 and GSK-3β phosphorylation in comparison to controls. Adding AG490, an inhibitor of JAK/STAT pathway, before I/R, prevented STAT-3 phosphorylation and abolished FDX-induced cardioprotection. On the contrary, FDX did not have an effect on infarct size or hemodynamic parameters in the isolated-heart model. Fondaparinux decreased I/R injury in vivo, but not in a crystalloid-perfused isolated heart. Under our experimental conditions, FDX required whole blood to be protective, and this beneficial effect was mediated through STAT-3 phosphorylation.
急性心肌梗死是全球范围内导致死亡和发病的主要原因。尽管心肌再灌注对于成功恢复至关重要，但与再灌注损伤相关。有两种主要的细胞存活信号级联反应被认为可以对抗缺血再灌注（I / R）损伤：再灌注损伤挽救激酶，包括 Akt、细胞外信号调节激酶 1/2 和下游靶标 GSK-3β，以及生存激活因子增强，涉及 STAT-3。已经表明，因子 Xa 的药理学抑制可减轻 I / R 损伤，但细胞机制尚不清楚。我们的目的是确定全血在依诺肝素（FDX）诱导的心脏保护中的作用，以及再灌注损伤挽救激酶和生存激活因子增强途径的参与。我们使用短暂性冠状动脉结扎大鼠模型和晶体灌注分离大鼠心脏模型在体内和体外研究了 FDX 预防体内 I / R 损伤的能力。在两种模型中，在再灌注 120 分钟后评估梗塞面积。在再灌注 15 和 30 分钟后收集心肌组织，进行 Western blot 分析。在体内，与对照组相比，FDX 可使梗塞面积减少 29％，并诱导明显的 STAT-3 和 GSK-3β磷酸化。在 I / R 之前添加 JAK / STAT 途径抑制剂 AG490 可防止 STAT-3 磷酸化并消除 FDX 诱导的心脏保护作用。相反，FDX 对离体心脏模型中的梗塞面积或血液动力学参数没有影响。FDX 在体内降低了 I / R 损伤，但在晶体灌注分离的心脏中没有作用。在我们的实验条件下，FDX 需要全血才能发挥保护作用，这种有益作用是通过 STAT-3 磷酸化介导的。
