Sphingosine-1-Phosphate Receptor Agonist Fingolimod Increases Myocardial Salvage and Decreases Adverse Postinfarction Left Ventricular Remodeling in a Porcine Model of Ischemia/Reperfusion
Sphingosine-1-Phosphate Receptor Agonist Fingolimod Increases Myocardial Salvage and Decreases Adverse Postinfarction Left Ventricular Remodeling in a Porcine Model of Ischemia/Reperfusion
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DOI：
10.1161/circulationaha.115.012427
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发表时间：
2016-03-08
期刊：
影响因子：
37.8
通讯作者：
Badimon, Juan J.
中科院分区：
文献类型：
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作者：
Santos-Gallego, Carlos G.;Vahl, Torsten P.;Badimon, Juan J.
背景-Fingolimod是一种鞘氨醇-1-磷酸受体激动剂，用于治疗多发性硬化症，并发挥抗细胞凋亡的特性。我们假设，在猪急性心肌梗死(MI)期间用Fingolimod激活鞘氨醇-1-磷酸受体可抑制细胞凋亡，从而增加心肌挽救，缩小梗死面积，减轻猪左室(LV)重构。方法和结果-通过球囊结扎左前降支，然后再灌流，诱导猪缺血/再灌注。动物随机接受Fingolimod或生理盐水(对照组)。在短期实验中，Fingolimod治疗在MI后24小时激活了心肌保护再灌注损伤挽救激酶和Survior激活因子增强通路，导致心肌细胞凋亡减少，心肌氧化应激减少。这些作用均被两条通路的特异性抑制剂所阻断，表明Fingolimod的心肌保护作用是通过再灌注损伤挽救激酶和Survior激活因子增强通路介导的。在长期实验中，Fingolimod显著改善了心肌挽救，缩小了梗死范围，并改善了心梗后1周和1个月的心脏磁共振测量的收缩左心功能。重要的是，Fingolimod减轻了MI后1个月不良左室重构的发展。具体地说，Fingolimod治疗显著减少了左室质量、左室扩张和神经激素激活，并保留了左室几何形状。此外，Fingolimod可减少心肌梗死后远端非梗死区myocardium.Conclusions-Sphingosine-1-phosphate受体激活中的间质纤维化、心肌细胞肥大、Akt和细胞外受体K1/2的慢性激活，并通过再灌注损伤挽救激酶和Survior激活因子增强通路缩小梗塞范围，改善收缩功能，减轻MI后LV重构。我们的数据有力地支持了心肌梗死期间鞘氨醇-1-磷酸受体的激活对心脏的保护作用。
Background-Fingolimod, a sphingosine-1-phosphate receptor agonist, is used for the treatment of multiple sclerosis and exerts antiapoptotic properties. We hypothesized that sphingosine-1-phosphate receptor activation with fingolimod during acute myocardial infarction (MI) inhibits apoptosis, leading to increased myocardial salvage, reduced infarct size, and mitigated left ventricular (LV) remodeling in a porcine model of ischemia/reperfusion.Methods and Results-Ischemia/reperfusion was induced in pigs by balloon occlusion of the left anterior descending artery, followed by reperfusion. Animals randomly received fingolimod or saline (control). In short-term experiments, fingolimod treatment activated the cardioprotective reperfusion injury salvage kinase and survivor activating factor enhancement pathways in the infarct border zone 24 hours after MI, leading to decreased cardiomyocyte apoptosis and reduced myocardial oxidative stress. These effects were abolished by specific inhibitors of both pathways, demonstrating that fingolimod-induced cardioprotection was mediated by reperfusion injury salvage kinase and survivor activating factor enhancement pathways. In long-term experiments, fingolimod significantly improved myocardial salvage, reduced infarct size, and improved systolic LV function measured by cardiac magnetic resonance 1 week and 1 month after MI. Importantly, fingolimod mitigated the development of adverse post-MI LV remodeling 1 month after MI. Specifically, fingolimod treatment led to a significant reduction in LV mass, LV dilatation, and neurohormonal activation, and it preserved LV geometry. Furthermore, fingolimod decreased interstitial fibrosis, cardiomyocyte hypertrophy, and chronic activation of Akt and extracellular receptor kinase 1/2 in the remote noninfarcted myocardium.Conclusions-Sphingosine-1-phosphate receptor activation with fingolimod during acute MI reduced infarct size via the reperfusion injury salvage kinase and survivor activating factor enhancement pathways, improved systolic LV function, and mitigated post-MI LV remodeling. Our data strongly support a cardioprotective role for sphingosine-1-phosphate receptor activation during MI.