Metformin prevents high-glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process
Metformin prevents high-glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process
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DOI：
10.2337/diabetes.54.7.2179
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发表时间：
2005-07-01
期刊：
影响因子：
7.7
通讯作者：
Leverve, X
中科院分区：
文献类型：
--
作者：
Detaille, D;Guigas, B;Leverve, X
高血糖诱导的氧化应激对内皮细胞有害，导致糖尿病的血管并发症。线粒体通透性转换孔（PTP）是一种参与细胞死亡的氧化应激敏感通道，因此，我们研究了其在内皮细胞暴露于氧化应激或高葡萄糖水平中的潜在作用。二甲双胍，一种用于2型糖尿病的降糖药，也被研究，因为它抑制转化细胞系中的PTP开放。参比PTP抑制剂环孢素A（CsA）和治疗剂量的二甲双胍（100 μ mol/l）导致透化人微血管内皮细胞（HMEC-1）中的PTP抑制。此外，将完整的HMEC-1或来自人脐静脉或牛主动脉的原代内皮细胞暴露于氧化剂叔丁基过氧化氢或30 mmol/l葡萄糖引发PTP开放、细胞色素c分解和细胞死亡。CsA或二甲双胍可预防所有这些效应。抗氧化剂N-乙酰-L-半胱氨酸也可防止高血糖诱导的细胞凋亡。我们得出结论：1）葡萄糖浓度升高导致氧化应激，有利于几种内皮细胞类型的PTP开放和随后的细胞死亡，2）二甲双胍可预防这种PTP开放相关的细胞死亡。我们认为二甲双胍通过降低血糖及其对PTP调节的作用改善糖尿病相关血管疾病。
Hyperglycemia-induced oxidative stress is detrimental for endothelial cells, contributing to the vascular complications of diabetes. The mitochondrial permeability transition pore (PTP) is an oxidative stress-sensitive channel involved in cell death; therefore, we have examined its potential role in endothelial cells exposed to oxidative stress or high glucose level. Metformin, an antihyperglycemic agent used in type 2 diabetes, was also investigated because it inhibits PTP opening in transformed cell lines. Cyclosporin A (CsA), the reference PTP inhibitor, and a therapeutic dose of metformin (100 mu mol/l) led to PTP inhibition in permeabilized human microvascular endothelial cells (HMEC-1). Furthermore, exposure of intact HMEC-1 or primary endothelial cells from either human umbilical vein or bovine aorta to the oxidizing agent tert-butylhydroperoxide or to 30 mmol/l glucose triggered PTP opening, cytochrome c decompartmentalization, and cell death. CsA or metformin prevented all of these effects. The antioxidant N-acetyl-L-eysteine also prevented hyperglycemia-induced apoptosis. We conclude that 1) elevated glucose concentration leads to an oxidative stress that favors PTP opening and subsequent cell death in several endothelial cell types and 2) metformin prevents this PTP opening-related cell death. We propose that metformin improves diabetes-associated vascular disease both by lowering blood glucose and by its effect on PTP regulation.