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GW501516对低氧致肺动脉内皮细胞损伤的影响及机制
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| 篇名： | GW501516对低氧致肺动脉内皮细胞损伤的影响及机制 |
| TITLE： | Effects of GW501516 on the injury of pulmonary artery endothelial cells induced by hypoxia and its mechanism |
| 摘要： | 目的 探讨过氧化物酶体增殖物激活受体δ（PPARδ）激动剂GW501516对低氧诱导的肺动脉内皮细胞（PAECs）损伤的影响及机制。方法通过检测PAECs的相对存活率，观察GW501516的细胞毒性作用；采用Westernblot法检测PPARδ蛋白的表达水平。建立低氧条件下PAECs损伤的细胞模型，以抗氧化剂N-乙酰半胱氨酸（NAC）为阳性对照，通过检测细胞凋亡率、细胞活力、乳酸脱氢酶（LDH）活性、活性氧（ROS）水平，考察GW501516对细胞损伤及ROS产生的影响。以核因子E2相关因子2（Nrf2）激活剂富马酸二甲酯（DMF）为阳性对照，在低氧条件下通过GW501516和（或）Nrf2抑制剂ML385孵育PAECs，以细胞损伤（细胞凋亡、细胞活力、LDH活性）及超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GPx）、过氧化氢酶（CAT）、丙二醛（MDA）、ROS水平及Nrf2、血红素加氧酶1（HO-1）、裂解型胱天蛋白酶3（C-caspase-3）蛋白的表达水平，探讨GW501516对低氧致PAECs损伤的作用机制。结果低氧刺激能够抑制PAECs内PPARδ蛋白的表达（P＜0.05），而GW501516可在低氧条件下促进PPARδ蛋白的表达且无明显的细胞毒性作用。GW501516可抑制PAECs凋亡，提高细胞活力，降低LDH活性及ROS水平。GW501516可通过激活Nrf2通路，上调PAECs内HO-1蛋白表达水平及SOD、GPx、CAT水平，降低MDA、ROS水平（P＜0.05），而Nrf2抑制剂ML385能够逆转GW501516的上述作用（P＜0.05）。GW501516下调C-caspase-3蛋白表达，抑制低氧诱导的PAECs损伤的作用与Nrf2激活剂DMF相似（P＜0.05），而Nrf2抑制剂ML385能够逆转GW501516抑制PAECs损伤的作用（P＜0.05）。结论GW501516可通过抑制氧化应激来减轻低氧诱导的PAECs损伤，其机制与激活Nrf2有关。 |
| ABSTRACT： | OBJECTIVE To investigate the effects of the peroxisome proliferator-activated receptors δ （PPARδ） agonist GW501516 on the injury of pulmonary artery endothelial cells （PAECs） induced by hypoxia and its mechanism. METHODS The cytotoxic effects of GW501516 were observed by detecting the relative survival rate of PAECs； the protein expression of PPARδ was determined by Western blot assay. The cellular model of PAECs injury was established under hypoxic conditions； using antioxidant N-acetylcysteine （NAC） as positive control， the effects of GW501516 on cell injury and reactive oxygen species （ROS） production were investigated by detecting cell apoptotic rate， cell viability， lactate dehydrogenase （LDH） activity and ROS levels. Using nuclear factor erythroid 2-related factor 2（Nrf2） activator dimethyl fumarate （DMF） as positive control， PAECs were incubated with GW501516 and/or Nrf2 inhibitor ML385 under hypoxic conditions； the mechanism of GW501516 on PAECs injury induced by hypoxia was investigated by detecting cell injury （cell apoptosis， cell viability， LDH activity）， the levels of superoxide dismutase （SOD）， glutathione peroxidase （GPx）， catalase （CAT）， malondialdehyde （MDA） and ROS， the expressions of Nrf2， heme oxygenase-1 （HO-1） and cleaved-caspase-3 （C-caspase-3） protein. RESULTS The results demonstrated that hypoxia inhibited the protein expression of PPARδ （P＜0.05）， while GW501516 promoted the protein expression of PPARδ in hypoxia- exposed PAECs without obvious cytotoxic effects. GW501516 inhibited the apoptosis of PAECs， improved cell viability， and reduced LDH activity and ROS levels. GW501516 could up-regulate the protein expression of HO-1 in PAECs and the levels of SOD， GPx and CAT， while down-regulated the levels of MDA and ROS by activating the Nrf2 pathway （P＜0.05）； but Nrf2 inhibitor ML385 could reverse the above effects of GW501516 （P＜0.05）. GW501516 exerted similar effects to Nrf2 activator DMF in down-regulating the expression of C-caspase-3 and inhibiting the injury of PAECs under conditions of hypoxia （P＜0.05）. Moreover， Nrf2 inhibitor ML385 reversed the 163.com inhibition effects of GW501516 on PAECs injury （P＜0.05）. CONCLUSIONS GW501516 can relieve the hypoxia-induced injury of PAECs via the inhibition of oxidative stress， the mechanism of which may be associated with activating Nrf2. |
| 期刊： | 2024年第35卷第02期 |
| 作者： | 陈昌贵；易春峰；余志华；王栋；李立为；贺立群 |
| AUTHORS： | CHEN Changgui，YI Chunfeng，YU Zhihua，WANG Dong，LI Liwei，HE Liqun |
| 关键字： | GW501516；低氧；肺动脉内皮细胞；氧化应激；损伤；核因子E2相关因子2 |
| KEYWORDS： | GW501516； hypoxia； pulmonary artery endothelial cells； oxidative stress； injury； nuclear factor erythroid 2- |
| 阅读数： | 163 次 |
| 本月下载数： | 68 次 |
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