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首页> 外文期刊>Clinical and experimental pharmacology & physiology >Mechanism of sphingosine-1-phosphate induced cardioprotection against I/R injury in diabetic rat heart: Possible involvement of glycogen synthase kinase 3β and mitochondrial permeability transition pore
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Mechanism of sphingosine-1-phosphate induced cardioprotection against I/R injury in diabetic rat heart: Possible involvement of glycogen synthase kinase 3β and mitochondrial permeability transition pore

机译：鞘氨醇-1-磷酸诱导的糖尿病大鼠心脏抗I / R损伤的机制：糖原合酶激酶3β和线粒体通透性过渡孔的可能参与

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There is growing evidence that diabetes mellitus causes attenuation of the bioactive metabolite of membrane sphingolipids, sphingosine-1-phosphate, and this may be a key mechanism in the decreased cardioprotective effect of ischaemic preconditioning (IPC) in the diabetic heart. Thus, this study has been designed to investigate the role and pharmacological potential of sphingosine-1-phosphate in diabetic rat heart. Diabetes was produced in Wistar rats by administration of a low dose of streptozotocin (STZ) (35 mg/kg, i.p., once) and feeding a high fat diet (HFD) for 6 weeks. Isolated rat heart was subjected to 30 min ischaemia followed by 120 min of reperfusion (I/R). The heart was subjected to pre-ischaemic treatment (before ischaemia for 20 min) and pharmacological preconditioning with the S1P agonist FTY720 (0.6 μmol/L) with and without atractyloside (an mPTP opener; in the last episode of reperfusion before I/R). Myocardial infarction was assessed in terms of increase in lactate dehydrogenase (LDH), creatinine kinase-MB (CK-MB), myeloperoxidase (MPO) level and infarct size (triphenyltetrazolium chloride staining). Immunohistochemistry analysis was done for assessment of tumour necrosis factor (TNF)-α and glycogen synthase kinase (GSK)-3β level in cardiac tissue. Pre-ischaemic treatment and pharmacological preconditioning with FTY720 significantly decreased I/R-induced myocardial infarction, TNF-alpha, GSK-3β level and release of LDH and CK-MB as compared to control group. The cardioprotective effect of S1P agonist was significantly attenuated by atractyloside. It may be concluded that S1P agonist FTY720 prevents the diabetic heart from ischaemic reperfusion injury, possibly through inhibition of GSK-3β and regulation of opening of mitochondrial permeability transition pore.
机译：越来越多的证据表明，糖尿病会导致膜鞘糖脂-1磷酸鞘氨醇的生物活性代谢产物减弱，这可能是降低糖尿病心脏缺血预处理（IPC）的心脏保护作用的关键机制。因此，本研究旨在研究1-磷酸鞘氨醇在糖尿病大鼠心脏中的作用和药理潜力。在Wistar大鼠中，糖尿病是通过低剂量的链脲佐菌素（STZ）（35 mg / kg，腹腔一次）和高脂饮食（HFD）喂养6周来产生的。离体的大鼠心脏经受30分钟的局部缺血，然后进行120分钟的再灌注（I / R）。对心脏进行缺血前治疗（缺血前20分钟），并用S1P激动剂FTY720（0.6μmol/ L）在有和没有白术苷的情况下进行药理预处理（mPTP开放剂;在I / R之前的最后一次灌注中） 。根据乳酸脱氢酶（LDH），肌酐激酶-MB（CK-MB），髓过氧化物酶（MPO）水平和梗塞大小（三苯基氯化四氮唑染色）的增加来评估心肌梗塞。进行了免疫组织化学分析，以评估心脏组织中的肿瘤坏死因子（TNF）-α和糖原合酶激酶（GSK）-3β的水平。与对照组相比，缺血前治疗和FTY720的药物预处理可显着降低I / R诱导的心肌梗塞，TNF-α，GSK-3β水平以及LDH和CK-MB的释放。白术苷可显着减弱S1P激动剂的心脏保护作用。可以得出结论，S1P激动剂FTY720可能通过抑制GSK-3β和调节线粒体通透性过渡孔的开放来预防糖尿病心脏缺血再灌注损伤。

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