Human thrombopoietin reduces myocardial infarct size, apoptosis, and stunning following ischaemia/reperfusion in rats
Human thrombopoietin reduces myocardial infarct size, apoptosis, and stunning following ischaemia/reperfusion in rats
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DOI：
10.1093/cvr/cvm026
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发表时间：
2008-01-01
影响因子：
10.8
通讯作者：
Gross, Garrett J.
中科院分区：
文献类型：
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作者：
Baker, John E.;Su, Jidong;Gross, Garrett J.
血小板生成素（Thrombopoietin，Tpo）具有刺激血小板生成的作用.然而，它是目前未知的TPO是否发挥生理功能，在heart.Methods和结果，我们评估了潜在的保护作用，TPO在体外和体内的两个大鼠模型的心肌缺血/再灌注。RT-PCR检测心肌组织中Tpo受体（c-mpl）的表达，Western blotting和免疫组化检测Tpo受体蛋白的表达。TPO治疗缺血前立即减少心肌坏死，细胞凋亡，并在缺血/再灌注后在大鼠心室功能下降的浓度和剂量依赖性的方式与1.0 ng/mL的体外最佳浓度和0.05 μ g/kg iv在体内的最佳剂量。在缺血发作后或再灌注时给予Tpo也能减少梗死面积。Tpo在再灌注期间激活JAK-2（Janus激酶-2）和p44 MAN（丝裂原活化蛋白激酶），但在缺血前不激活。JAK-2（AG-490）、p42/44 MAPK（PD 98059）、线粒体K-ATP通道（5-HD）和肌膜K-ATP通道（HMR 1098）的抑制消除了TPO诱导的对心肌缺血/再灌注损伤的抵抗。AG-490、PD 98059、5-HD和HMR 1098单独使用对心脏保护没有影响。Tpo单次给药（0.05或1.0 μ g/kg iv）16 d内血小板计数或红细胞压积均未升高。结论Tpo单次给药通过JAK-2、p42/44 MAPK和K-ATP通道发挥心脏保护作用，提示Tpo在治疗心肌缺血再灌注损伤中具有潜在的治疗作用。
Aims Thrombopoietin (Tpo) is known for its ability to stimulate platelet production. However, it is currently unknown whether Tpo plays a physiological function in the heart.Methods and results We assessed the potential protective role of Tpo in vitro and in vivo in two rat models of myocardial ischaemia/reperfusion. Tpo receptor (c-mpl) message was detected in the heart using RT-PCR, and the Tpo receptor protein was detected using western blotting and immunohistochemistry. Tpo treatment immediately before ischaemia reduced myocardial necrosis, apoptosis, and decline in ventricular function following ischaemia/reperfusion in the rat in a concentration- and dose-dependent manner with an optimal concentration of 1.0 ng/mL in vitro and an optimal dose of 0.05 mu g/kg iv in vivo. Tpo also reduced infarct size when given after the onset of ischaemia or at reperfusion. Tpo activated JAK-2 (Janus kinase-2) and p44 MAN (mitogen-activated protein kinase) during reperfusion but not prior to ischaemia. Inhibition of JAK-2 (AG-490), p42/44 MAPK (PD98059), mitochondrial K-ATP channels (5-HD), and sarcolemmat K-ATP channels (HMR 1098) abolished Tpo-induced resistance to injury from myocardial ischaemia/reperfusion. AG-490, PD98059, 5-HD, and HMR1098 alone had no effect on cardioprotection. Treatment with a single dose of Tpo (0.05 or 1.0 mu g/kg iv) did not result in the elevation of platelet count or haematocrit over a 16-day period.Conclusion A single treatment of Tpo confers cardioprotection through JAK-2, p42/44 MAPK, and K-ATP channels, suggesting a potential therapeutic role of Tpo in the treatment of injury resulting from myocardial ischaemia and reperfusion.