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首页> 外文期刊>Cell death discovery. >Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration
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Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration

机译:伊美林明通过抑制线粒体通透性转变而不抑制线粒体呼吸作用来预防人内皮细胞死亡

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摘要

Imeglimin is the first in a new class of oral glucose-lowering agents, having recently completed its phase 2b trial. As Imeglimin did show a full prevention of β-cell apoptosis, and since angiopathy represents a major complication of diabetes, we studied Imeglimin protective effects on hyperglycemia-induced death of human endothelial cells (HMEC-1). These cells were incubated in several oxidative stress environments (exposure to high glucose and oxidizing agent tert -butylhydroperoxide) which led to mitochondrial permeability transition pore (PTP) opening, cytochrome c release and cell death. These events were fully prevented by Imeglimin treatment. This protective effect on cell death occurred without any effect on oxygen consumption rate, on lactate production and on cytosolic redox or phosphate potentials. Imeglimin also dramatically decreased reactive oxygen species production, inhibiting specifically reverse electron transfer through complex I. We conclude that Imeglimin prevents hyperglycemia-induced cell death in HMEC-1 through inhibition of PTP opening without inhibiting mitochondrial respiration nor affecting cellular energy status. Considering the high prevalence of macrovascular and microvascular complications in type 2 diabetic subjects, these results together suggest a potential benefit of Imeglimin in diabetic angiopathy.
机译:Imeglimin是新型口服降糖药中的第一个,最近完成了其2b期试验。由于Imeglimin确实可以完全预防β细胞凋亡,并且由于血管病是糖尿病的主要并发症,因此我们研究了Imeglimin对高血糖诱导的人内皮细胞(HMEC-1)死亡的保护作用。这些细胞在几种氧化应激环境(暴露于高葡萄糖和氧化剂叔丁基氢过氧化物)中孵育,这导致线粒体通透性转换孔(PTP)打开,细胞色素c释放和细胞死亡。依格列明治疗完全预防了这些事件。这种对细胞死亡的保护作用对氧的消耗速率,乳酸的产生以及胞质的氧化还原或磷酸电位没有任何影响。 Imeglimin还显着降低了活性氧的产生,从而特别抑制了通过复合物I的反向电子转移。我们得出的结论是,Imeglimin通过抑制PTP的开放而不抑制线粒体呼吸作用或影响细胞能量状态,防止了高血糖诱导的HMEC-1细胞死亡。考虑到2型糖尿病患者中大血管和微血管并发症的患病率较高,这些结果共同提示了伊格列明在糖尿病性血管病中的潜在益处。

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