Monosialoganglioside-Containing Nanoliposomes Restore Endothelial Function Impaired by AL Amyloidosis Light Chain Proteins.
Monosialoganglioside-Containing Nanoliposomes Restore Endothelial Function Impaired by AL Amyloidosis Light Chain Proteins.
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DOI：
10.1161/jaha.116.003318
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发表时间：
2016-06-13
影响因子：
5.4
通讯作者：
Migrino RQ
中科院分区：
文献类型：
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作者：
Franco DA;Truran S;Weissig V;Guzman-Villanueva D;Karamanova N;Senapati S;Burciu C;Ramirez-Alvarado M;Blancas-Mejia LM;Lindsay S;Hari P;Migrino RQ
轻链淀粉样变性（AL）与高死亡率相关，特别是在晚期心血管受累患者中。它是由血管、心脏和其他组织中错误折叠的轻链蛋白（LC）的毒性引起的。没有逆转LC组织毒性的治疗。我们测试了由单唾液酸神经节苷脂、磷脂酰胆碱和胆固醇组成的纳米脂质体（含GM 1神经节苷脂的纳米脂质体[NLGM 1]）可以保护LC诱导的人类微血管功能障碍的假设，并评估了保护作用背后的机制。在暴露于含或不含NLGM 1的LC（20 μg/mL）（LC：NLGM 1质量比为1：10）之前和之后，测量了来自无AL的人类参与者的离体腹部脂肪小动脉对乙酰胆碱和罂粟碱的扩张反应。将人脐静脉内皮细胞暴露于溶媒、含或不含NLGM 1的LC或NLGM 1 18至20小时，并比较氧化和硝化应激反应和细胞活力。LC损害了小动脉扩张剂对乙酰胆碱的反应，通过与NLGM 1联合治疗恢复。LC降低内皮细胞一氧化氮的产生和细胞活力，同时增加超氧化物和过氧亚硝酸盐，这些不利影响被逆转NLGM 1。NLGM 1增加抗氧化酶血红素加氧酶1和NAD（P）H醌脱氢酶1的内皮细胞蛋白表达，并增加核因子红细胞2样2（Nrf-2）蛋白。Nrf-2基因敲低降低了抗氧化应激反应，并逆转了NLGM 1的保护作用。NLGM 1通过增加一氧化氮生物利用度和减少Nrf-2依赖性抗氧化应激反应介导的氧化和硝化应激，保护LC诱导的人类微血管内皮功能障碍。这些发现为轻链淀粉样变性提供了一种潜在的新治疗方法。
Light chain amyloidosis (AL) is associated with high mortality, especially in patients with advanced cardiovascular involvement. It is caused by toxicity of misfolded light chain proteins (LC) in vascular, cardiac, and other tissues. There is no treatment to reverse LC tissue toxicity. We tested the hypothesis that nanoliposomes composed of monosialoganglioside, phosphatidylcholine, and cholesterol (GM1 ganglioside–containing nanoliposomes [NLGM1]) can protect against LC‐induced human microvascular dysfunction and assess mechanisms behind the protective effect. The dilator responses of ex vivo abdominal adipose arterioles from human participants without AL to acetylcholine and papaverine were measured before and after exposure to LC (20 μg/mL) with or without NLGM1 (1:10 ratio for LC:NLGM1 mass). Human umbilical vein endothelial cells were exposed for 18 to 20 hours to vehicle, LC with or without NLGM1, or NLGM1 and compared for oxidative and nitrative stress response and cellular viability. LC impaired arteriole dilator response to acetylcholine, which was restored by co‐treatment with NLGM1. LC decreased endothelial cell nitric oxide production and cell viability while increasing superoxide and peroxynitrite; these adverse effects were reversed by NLGM1. NLGM1 increased endothelial cell protein expression of antioxidant enzymes heme oxygenase 1 and NAD(P)H quinone dehydrogenase 1 and increased nuclear factor, erythroid 2 like 2 (Nrf‐2) protein. Nrf‐2 gene knockdown reduced antioxidant stress response and reversed the protective effects of NLGM1. NLGM1 protects against LC‐induced human microvascular endothelial dysfunction through increased nitric oxide bioavailability and reduced oxidative and nitrative stress mediated by Nrf‐2–dependent antioxidant stress response. These findings point to a potential novel therapeutic approach for light chain amyloidosis.