The protective role of isorhamnetin on human brain microvascular endothelial cells from cytotoxicity induced by methylglyoxal and oxygen-glucose deprivation
The protective role of isorhamnetin on human brain microvascular endothelial cells from cytotoxicity induced by methylglyoxal and oxygen-glucose deprivation
复制标题
异鼠李素对人脑微血管内皮细胞免受甲基乙二醛和氧糖剥夺诱导的细胞毒性的保护作用
DOI：
10.1111/jnc.13436
复制
发表时间：
2016-02-01
影响因子：
4.7
通讯作者：
Dai, Haibin
中科院分区：
文献类型：
--
作者：
Li, Wenlu;Chen, Zhigang;Dai, Haibin
脑血管内皮细胞作为脑卒中的第一靶点，在脑血管修复和维护中起着关键作用，而糖尿病时其功能受到阻碍。甲基乙二醛（MGO）是葡萄糖代谢过程中产生的反应性二羰基，在糖尿病患者体内蓄积。MGO及其诱导的晚期糖基化终产物（AGEs）可减轻脑卒中后脑血管损伤，与内皮细胞功能障碍密切相关。采用MGO加氧糖剥夺（OGD）模拟糖尿病脑卒中，观察异鼠李素对OGD诱导的原代人脑微血管内皮细胞（HBMEC）细胞毒性的保护作用，并探讨其机制。MGO处理24 h可显著增强OGD诱导的HBMEC 3 h毒性效应，而异鼠李素（100 μ mol/L）预处理可抑制该效应。此外，异鼠李素的保护作用是多功能依赖性的，其包括抗炎、抗氧化应激和抗凋亡作用。除了其众所周知的抑制作用对细胞凋亡依赖性或内在途径，异鼠李素还减少了激活的外源性凋亡途径，其特征在于减少的表达和活性的半胱天冬酶3和半胱天冬酶8。此外，异鼠李素预处理特异性抑制FAS/FASL表达，抑制核因子-κ B核转位。总之，我们的研究结果表明，异鼠李素保护OGD诱导的细胞毒性后，MGO处理在培养的HBMEC由于其多重保护作用，并能抑制Fas介导的外源性凋亡。因此，异鼠李素是一种很有前途的治疗高血糖和缺血性脑血管变性的药物。
As the first target of stroke, cerebral endothelial cells play a key role in brain vascular repair and maintenance, and their function is impeded in diabetes. Methylglyoxal (MGO), a reactive dicarbonyl produced during glucose metabolism, accumulates in diabetic patients. MGO and MGO-induced advanced glycation end-products (AGEs) could ameliorate stroke-induced brain vascular damage, closely related with ECs dysfunction. Using MGO plus oxygen-glucose deprivation (OGD) to mimic diabetic stroke, we reported the protective effect of isorhamnetin on OGD induced cytotoxicity after MGO treatment on primary human brain microvascular endothelial cells (HBMEC) and explored the underlying mechanisms. Treatment of MGO for 24 h significantly enhanced 3-h OGD-induced HBMEC toxic effect, which was inhibited by pretreatment of isorhamnetin (100 mu mol/L). Moreover, the protective effect of isorhamnetin is multiple function dependent, which includes anti-inflammation, anti-oxidative stress and anti-apoptosis effects. Besides its well-known inhibition on the mitochondria-dependent or intrinsic apoptotic pathway, isorhamnetin also reduced activation of the extrinsic apoptotic pathway, as characterized by the decreased expression and activity of caspase 3 and caspase 8. Furthermore, pretreatment with isorhamnetin specifically inhibited FAS/FASL expression and suppressed nuclear factor-kappa B nuclear translocation. Taken together, our results indicated that isorhamnetin protected against OGD-induced cytotoxicity after MGO treatment in cultured HBMEC due to its multiple protective effects and could inhibit Fas-mediated extrinsic apoptosis. Therefore, isorhamnetin is a promising reagent for the treatment of hyperglycemia and ischemia-induced cerebral vascular degeneration.