Nanoliposomes protect against AL amyloid light chain protein-induced endothelial injury.
Nanoliposomes protect against AL amyloid light chain protein-induced endothelial injury.
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DOI：
10.3109/08982104.2013.838258
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发表时间：
2014-03
影响因子：
4.4
通讯作者：
Migrino RQ
中科院分区：
文献类型：
--
作者：
Truran S;Weissig V;Ramirez-Alvarado M;Franco DA;Burciu C;Georges J;Murarka S;Okoth WA;Schwab S;Hari P;Migrino RQ
轻链淀粉样变性（AL）的一种新认识的致病机制涉及错误折叠的轻链蛋白（LC）引起的内皮功能障碍和细胞损伤。纳米脂质体（NL）是一种人工磷脂囊泡，可以附着在错误折叠的蛋白质上，减少组织损伤。测试与NL共同治疗是否减少LC诱导的内皮功能障碍和细胞死亡。对14例非AL受试者的腹部皮下脂肪小动脉进行插管;在基线和暴露于LC（20 μg/mL，2例从AL受试者尿液中纯化，1例从人重组LC [AL-09]）± NL（磷脂酰胆碱/胆固醇/磷脂酸70/25/5摩尔比）或单独NL 1小时后，测量扩张器对乙酰胆碱和罂粟碱的反应。将人主动脉内皮细胞（HAEC）暴露于俄勒冈州绿标记的LC±NL 24小时，测定细胞内LC和凋亡（Hoechst染色）。在AL-09 LC±NL上进行圆二色光谱以跟踪二级结构和蛋白质热稳定性的变化。LC导致乙酰胆碱扩张受损，NL可恢复（对照-94.0± 1.8%，LC-65.0± 7.1%，LC+NL-95.3± 1.8%，p≤0.001 LC vs.对照或LC+NL）。NL保护作用可被L-NG-nitroarginine methyl ester抑制。NL增加LC的β折叠结构，减少LC的内皮细胞内化，并保护LC诱导的内皮细胞死亡。LC诱导人脂肪小动脉内皮功能障碍和内皮细胞死亡，与NL共同治疗可逆转。这种保护可能部分是由于增强LC蛋白结构和减少LC内化。纳米脂质体代表了一类有前途的新药物，以改善组织损伤的蛋白质错误折叠疾病，如AL。
A newly-recognized pathogenic mechanism underlying light chain amyloidosis (AL) involves endothelial dysfunction and cell injury caused by misfolded light chain proteins (LC). Nanoliposomes (NL) are artificial phospholipid vesicles that could attach to misfolded proteins and reduce tissue injury. To test whether co-treatment with NL reduce LC-induced endothelial dysfunction and cell death. Abdominal subcutaneous adipose arterioles from 14 non-AL subjects were cannulated; dilator response to acetylcholine and papaverine were measured at baseline and following 1-hour exposure to LC (20 μg/mL, 2 purified from AL subjects’ urine, 1 from human recombinant LC [AL-09]) ± NL (phosphatidylcholine/cholesterol/phosphatidic acid 70/25/5 molar ratio) or NL alone. Human aortic artery endothelial cells (HAEC) were exposed to Oregon Green-labeled LC±NL for 24 hours and intracellular LC and apoptosis (Hoechst stain) were measured. Circular dichroism spectroscopy was performed on AL-09 LC±NL to follow changes in secondary structure and protein thermal stability. LC caused impaired dilation to acetylcholine that was restored by NL (control-94.0±1.8%, LC-65.0±7.1%, LC+NL-95.3±1.8%, p≤0.001 LC vs. control or LC+NL). NL protection was inhibited by L-NG-nitroarginine methyl ester. NL increased the beta sheet structure of LC, reduced endothelial cell internalization of LC and protected against LC-induced endothelial cell death. LC induced human adipose arteriole endothelial dysfunction and endothelial cell death, which were reversed by co-treatment with NL. This protection may partly be due to enhancing LC protein structure and reducing LC internalization. Nanoliposomes represent a promising new class of agents to ameliorate tissue injury from protein misfolding diseases such as AL.
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DOI：
10.1016/j.echo.2009.09.012
发表时间：
2009-12
影响因子：
6.5
作者：
Migrino, Raymond Q.;Mareedu, Ravi K.;Eastwood, Daniel;Bowers, Mark;Harmann, Leanne;Hari, Parameswaran
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DOI：
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发表时间：
1999-03-30
影响因子：
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DOI：
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发表时间：
2011-12-01
影响因子：
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