Department of Cardiology and Office of Research, Phoenix Veterans Affairs Health Care System, AZ 85022, USA.
Am J Physiol Heart Circ Physiol. 2011 Dec;301(6):H2305-12. doi: 10.1152/ajpheart.00503.2011. Epub 2011 Sep 30.
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 μg/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.
轻链淀粉样变性（AL）涉及到淀粉样蛋白轻链蛋白（LC）的过度产生，导致心力衰竭，但组织毒性的机制仍不清楚。我们假设 LC 可诱导非 AL 人类微血管内皮功能障碍，并导致人心冠状动脉内皮细胞（HCAEC）凋亡损伤。从非 AL 患者中分离出脂肪动脉（n = 34，50 ± 3 岁）和心房冠状动脉（n = 19，68 ± 2 岁），并用乙酰胆碱/罂粟碱测量基础状态和 1 小时的 LC（20μg/ml）暴露时的扩张反应（来自活检证实的 AL 患者，年龄 57 ± 11 岁），并在抗氧化剂共处理的情况下进行测量。在 LC 暴露后测量冠状小动脉对缓激肽/罂粟碱的扩张反应。用 1 或 24 小时的 LC 暴露 HCAEC。LC 降低了脂肪小动脉中乙酰胆碱（10(-4) M：41.6 ± 7 对 85.8 ± 2.2%对照，P < 0.001）和罂粟碱（81.4 ± 4.6 对 94.8 ± 1.3%对照，P < 0.01）的扩张反应，而对缓激肽（10(-6) M：68.6 ± 6.2 对 90.9 ± 1.6%对照，P < 0.001）但不包括罂粟碱的扩张反应。在 LC 处理的小动脉中观察到超氧化物和过氧亚硝酸盐的增加。用聚乙二醇-超氧化物歧化酶和四氢生物蝶呤共处理可恢复脂肪小动脉的扩张，但仅部分恢复米托醌（线粒体靶向抗氧化剂）和 gp91ds-tat（NADPH 氧化酶抑制剂）。与对照相比，暴露于 LC 的 HCAEC 显示出减少的 NO 和增加的超氧化物、过氧亚硝酸盐、膜联蛋白-V 和碘化丙啶。生理浓度的 LC 短暂暴露可导致人心血管脂肪和冠状小动脉内皮功能障碍，并增加冠状血管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生成。微血管功能障碍和损伤是 AL 病理生物学的一种新机制，可能是治疗的潜在靶点。
