Oxidative Stress Alters the Morphology and Toxicity of Aortic Medial Amyloid.
Oxidative Stress Alters the Morphology and Toxicity of Aortic Medial Amyloid.
复制标题
氧化应激改变主动脉内侧淀粉样蛋白的形态和毒性。
DOI：
10.1016/j.bpj.2015.10.034
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发表时间：
2015-12-01
影响因子：
3.4
通讯作者：
Madine J
中科院分区：
文献类型：
--
作者：
Davies HA;Phelan MM;Wilkinson MC;Migrino RQ;Truran S;Franco DA;Liu LN;Longmore CJ;Madine J
淀粉样蛋白的聚集和纤维沉积与一系列神经退行性疾病和血管疾病相关，然而其潜在的分子机制却鲜为人知。在此，我们结合基于细胞的分析方法、生物物理分析以及原子力显微镜技术，来探究氧化应激在主动脉中膜淀粉样变（AMA）发病机制和沉积过程中的潜在作用。我们发现，AMA的主要成分——麦丁（medin），能够在人类细胞中诱导产生富含氧化物质的环境，增加超氧化物并降低生物可利用的一氧化氮。我们研究了这种氧化环境在改变麦丁聚集过程中可能发挥的作用，并确定了潜在的翻译后修饰位点，在这些位点上可明确证明存在位点特异性修饰和相互作用。在氧化环境中，麦丁的酪氨酸和色氨酸残基会发生硝化反应，由此对其形态产生影响，导致形成更长且毒性增强的纤维。这进一步促使我们去研究氧化应激在AMA致病性中的作用。
The aggregation and fibril deposition of amyloid proteins have been implicated in a range of neurodegenerative and vascular diseases, and yet the underlying molecular mechanisms are poorly understood. Here, we use a combination of cell-based assays, biophysical analysis, and atomic force microscopy to investigate the potential involvement of oxidative stress in aortic medial amyloid (AMA) pathogenesis and deposition. We show that medin, the main constituent of AMA, can induce an environment rich in oxidative species, increasing superoxide and reducing bioavailable nitric oxide in human cells. We investigate the role that this oxidative environment may play in altering the aggregation process of medin and identify potential posttranslational modification sites where site-specific modification and interaction can be unambiguously demonstrated. In an oxidizing environment, medin is nitrated at tyrosine and tryptophan residues, with resultant effects on morphology that lead to longer fibrils with increased toxicity. This provides further motivation to investigate the role of oxidative stress in AMA pathogenicity.