Human microvascular dysfunction and apoptotic injury induced by AL amyloidosis light chain proteins
Human microvascular dysfunction and apoptotic injury induced by AL amyloidosis light chain proteins
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DOI：
10.1152/ajpheart.00503.2011
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发表时间：
2011-12-01
影响因子：
4.8
通讯作者：
Hari, Parameswaran
中科院分区：
文献类型：
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作者：
Migrino, Raymond Q.;Truran, Seth;Hari, Parameswaran
Migrino RQ，Truran S，Gutterman DD，Franco DA，Bright M，Schlundt B，Timmons M，Motta A，菲利普斯SA，Hari P. AL淀粉样变性轻链蛋白诱导的人类微血管功能障碍和凋亡损伤。Am J Physiol Heart Circ Physiol 301：H2305-H2312，2011.首次发表于2011年9月30日; doi：10.1152/ajpheart.00503.2011.-轻链淀粉样变性（AL）涉及淀粉样轻链蛋白（LC）的过度产生，导致心力衰竭，但组织毒性的潜在机制仍不清楚。我们假设LC诱导非AL人微血管内皮功能障碍和人冠状动脉内皮细胞（HCAECs）凋亡损伤。对非AL受试者的脂肪小动脉（n = 34，50 +/- 3岁）和心房冠状小动脉（n = 19，68 +/- 2岁）进行插管。在基线和暴露于LC（20 μ g/ml）1小时时，测量了活检证实的AL受试者（57 +/- 11岁）对乙酰胆碱/罂粟碱的脂肪小动脉扩张反应，无和有抗氧化剂联合治疗。LC暴露后测量缓激肽/罂粟碱对冠状小动脉的扩张。将HCAEC暴露于1或24小时的LC。LC可减少乙酰胆碱（10（-4）M：41.6 +/- 7 vs. 85.8 +/- 2.2%对照，P < 0.001）和罂粟碱引起的扩张（81.4 +/- 4.6 vs. 94.8 +/- 1.3%对照组，P < 0.01）和缓激肽（10（-6）M：68.6 +/- 6.2 vs. 90.9 +/- 1.6%对照，P < 0.001），但冠状动脉中没有罂粟碱。有一个增加超氧化物和过氧亚硝酸盐与LC治疗的小动脉。聚乙二醇-超氧化物歧化酶和四氢生物蝶呤的共同治疗恢复了脂肪小动脉扩张，但只有部分恢复线粒体醌（线粒体靶向抗氧化剂）和gp 91 ds-tat（NADPH氧化酶抑制剂）。与对照组相比，暴露于LC的HCAECs显示NO减少，超氧化物、过氧亚硝酸盐、膜联蛋白-V和碘化丙啶增加。短暂暴露于生理量的LC诱导人脂肪和冠状动脉内皮功能障碍，并增加冠状动脉内皮细胞的凋亡损伤可能是由于氧化应激，NO生物利用度降低，和过氧亚硝酸盐的生产。微血管功能障碍和损伤是AL病理生物学的新机制，是治疗AL的潜在靶点。
Migrino RQ, Truran S, Gutterman DD, Franco DA, Bright M, Schlundt B, Timmons M, Motta A, Phillips SA, Hari P. Human microvascular dysfunction and apoptotic injury induced by AL amyloidosis light chain proteins. Am J Physiol Heart Circ Physiol 301: H2305-H2312, 2011. First published September 30, 2011; doi:10.1152/ajpheart.00503.2011.-Light chain amyloidosis (AL) involves overproduction of amyloidogenic light chain proteins (LC) leading to heart failure, yet the mechanisms underlying tissue toxicity remain unknown. We hypothesized that LC induces endothelial dysfunction in non-AL human microvasculature and apoptotic injury in human coronary artery endothelial cells (HCAECs). Adipose arterioles (n = 34, 50 +/- 3 yr) and atrial coronary arterioles (n = 19, 68 +/- 2 yr) from non-AL subjects were cannulated. Adipose arteriole dilator responses to acetylcholine/papaverine were measured at baseline and 1 h exposure to LC (20 mu g/ml) from biopsy-proven AL subjects (57 +/- 11 yr) without and with antioxidant cotreatment. Coronary arteriole dilation to bradykinin/papaverine was measured post-LC exposure. HCAECs were exposed to 1 or 24 h of LC. LC reduced dilation to acetylcholine (10(-4) M: 41.6 +/- 7 vs. 85.8 +/- 2.2% control, P < 0.001) and papaverine (81.4 +/- 4.6 vs. 94.8 +/- 1.3% control, P < 0.01) in adipose arterioles and to bradykinin (10(-6) M: 68.6 +/- 6.2 vs. 90.9 +/- 1.6% control, P < 0.001) but not papaverine in coronary arterioles. There was an increase in superoxide and peroxynitrite in arterioles treated with LC. Adipose arteriole dilation was restored by cotreatment with polyethylene glycol-superoxide dismutase and tetrahydrobiopterin but only partially restored by mitoquinone (mitochondria-targeted antioxidant) and gp91ds-tat (NADPH oxidase inhibitor). HCAECs exposed to LC showed reduced NO and increased superoxide, peroxynitrite, annexin-V, and propidium iodide compared with control. Brief exposure to physiological amounts of LC induced endothelial dysfunction in human adipose and coronary arterioles and increased apoptotic injury in coronary artery endothelial cells likely as a result of oxidative stress, reduced NO bioavailability, and peroxynitrite production. Microvascular dysfunction and injury is a novel mechanism underlying AL pathobiology and is a potential target for therapy.