背景:NOD样受体热蛋白结构域相关蛋白3(NOD-like receptor family,pyrin domain containing 3,NLRP3)炎性小体是否参与低氧对骨骼肌线粒体的损伤,及其相关机制尚不清楚.目的:观察NLRP3炎性小体特异性阻断剂VX-765对慢性低氧大鼠骨骼肌线粒体功能的影响,以探讨NLRP3炎性小体在低氧诱导骨骼肌线粒体损伤中的作用.方法:将30只SD大鼠随机分为常氧组、低氧组和低氧+VX-765组.低氧干预为低氧帐篷暴露,氧浓度设定为11.3％;VX-765干预为每日腹腔注射VX-765溶液1次,注射剂量为50 mg/kg,干预持续4周.结果与结论:VX-765显著抑制低氧暴露大鼠骨骼肌NLRP3和凋亡相关斑点样蛋白表达,降低caspase-1活性及白细胞介素1β含量,上调过氧化物酶体增殖物激活受体γ辅激活因子1α和细胞色素C氧化酶亚基Ⅳ表达,提高线粒体ATP合成活力和膜电位,抑制线粒体H2O2产生速率.结果表明,低氧可通过活化NLRP3炎性小体和损伤线粒体功能导致骨骼肌功能障碍,线粒体损伤产生大量活性氧,继而活化NLRP3炎性小体以促进白细胞介素1β等炎症因子的产生,而炎症因子可通过下调过氧化物酶体增殖物激活受体γ辅激活因子1α进一步造成线粒体损伤,NLRP3炎性小体活化和线粒体损伤之间形成恶性循环.%BACKGROUND:Whether NOD-like receptor family,pyrin domain containing 3 (NLRP3) inflammasome is involved in hypoxia-induced skeletal muscle mitochondrial dysfunction,and the underlying mechanism remain unclear.OBJECTIVE:To observe the effect of NLRP3 inflammasome inhibitor VX-765 on skeletal muscle mitochondrial function,and to explore the role of NLRP3 inflammasome in hypoxia-induced mitochondrial dysfunction.METHODS:Thirty Sprague-Dawley rats were randomly divided into three groups:normoxia,hypoxia,and hypoxia plus VX-765 groups.The rats in the hypoxia group were subjected to hypoxia exposure in normobaric hypoxic tent with 11.3％ O2.The hypoxia plus VX-765 group rats were given the intraperitoneal injection of VX-765 (50 mg/kg) daily.All of the interventions lasted for 4 weeks.RESULTS AND CONCLUSION:VX-765 in hypoxia markedly inhibited the expression of NLRP3 and apoptosis-associated speck-like protein,attenuated caspase-1 activity and interleukin-1β content,and suppressed mitochondrial H2O2 generation.In addition,VX-765 in hypoxia markedly enhanced the expression of mitochondrial peroxisome proliferator-activated receptor y coactivator 1-α and cyclooxygenase ⅣV,elevated mitochondrial membrane potent and ATP synthetase activity.These results indicate that hypoxia induces skeletal muscle dysfunction through activating NLRP3 inflammasome and impairing mitochondrial function.The hypoxia-induced mitochondrial dysfunction enhances reactive oxygen species generation and further triggers interleukin-1 β production via the NLRP3 inflammasome activation.In turn,interleukin-lβ further impairs mitochondrial function through suppresseing peroxisome proliferator-activated receptor y coactivator 1 o,resulting in a vicious circle between NLRP3 inflammasome activation and mitochondrial dysfunction.
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