INSERM U1082 IRTOMIT, Poitiers, France.
CHU Poitiers, Service d'hématologie biologique, Poitiers, France.
Shock. 2020 Jun;53(6):730-736. doi: 10.1097/SHK.0000000000001412.
Acute myocardial infarction is a leading cause of death worldwide. Though highly beneficial, reperfusion of myocardium is associated with reperfusion injury. While indirect inhibition of Factor Xa has been shown to attenuate myocardial ischemia-reperfusion (I/R) injury, the underlying mechanism remains unclear. Our study sought to evaluate the effect of rivaroxaban (RIV), a direct inhibitor of Factor Xa, on myocardial I/R injury and determine its cellular targets.
We used a rat model of 40-min coronary ligation followed by reperfusion. RIV (3 mg/kg) was given per os 1 h before reperfusion. Infarct size and myocardial proteic expression of survival pathways were assessed at 120 and 30 min of reperfusion, respectively. Plasmatic levels of P-selectin and von Willebrand factor were measured at 60 min of reperfusion. Cellular RIV effects were assessed using hypoxia-reoxygenation (H/R) models on human umbilical vein endothelial cells and on rat cardiomyoblasts (H9c2 cell line).
RIV decreased infarct size by 21% (42.9% vs. 54.2% in RIV-treated rats and controls respectively, P < 0.05) at blood concentrations similar to human therapeutic (387.7 ± 152.3 ng/mL) levels. RIV had no effect on H/R-induced modulation of endothelial phenotype, nor did it alter myocardial activation of reperfusion injury salvage kinase and survivor activating factor enhancement pathways at 30 min after reperfusion. However, RIV exerted a cytoprotective effect on H9c2 cells submitted to H/R.
RIV decreased myocardial I/R injury in rats at concentrations similar to human therapeutic ones. This protection was not associated with endothelial phenotype modulation but rather with potential direct cytoprotection on cardiomyocytes.
急性心肌梗死是全球范围内导致死亡的主要原因。尽管再灌注治疗具有高度的益处，但心肌再灌注与再灌注损伤相关。虽然间接抑制因子 Xa 已被证明可以减轻心肌缺血再灌注（I/R）损伤，但潜在机制尚不清楚。我们的研究旨在评估直接因子 Xa 抑制剂利伐沙班（RIV）对心肌 I/R 损伤的影响，并确定其细胞靶点。
我们使用了 40 分钟冠状动脉结扎后再灌注的大鼠模型。在再灌注前 1 小时给予 RIV（3mg/kg）口服。分别在再灌注 120 分钟和 30 分钟时评估梗死面积和存活途径的心肌蛋白表达。在再灌注 60 分钟时测量血浆 P-选择素和血管性血友病因子水平。使用人脐静脉内皮细胞和大鼠心肌细胞（H9c2 细胞系）的缺氧-复氧（H/R）模型评估细胞内 RIV 作用。
RIV 使梗死面积减少了 21%（RIV 治疗组为 42.9%，对照组为 54.2%，P<0.05），此时血浆浓度与人类治疗浓度（387.7±152.3ng/mL）相似。RIV 对 H/R 诱导的内皮表型改变没有影响，也没有改变再灌注损伤 salvage 激酶和幸存者激活因子增强途径在再灌注后 30 分钟的心肌激活。然而，RIV 对 H9c2 细胞的 H/R 具有细胞保护作用。
RIV 在与人类治疗浓度相似的浓度下减少了大鼠的心肌 I/R 损伤。这种保护与内皮表型调节无关，而是与潜在的心肌细胞直接保护作用有关。
