Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
Department of Molecular Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Geriatr Gerontol Int. 2019 Oct;19(10):1054-1062. doi: 10.1111/ggi.13757. Epub 2019 Aug 21.
Human vascular senescence, which mainly occurs in media, is not completely understood. Here, we used proteomic approaches to investigate age-associated changes in human aortic media with the goal of understanding the molecular mechanisms underlying vascular senescence.
Cryopreserved autopsy samples of aortic media from older-aged (aged 70-100 years, n = 25), middle-aged (aged 49-68 years, n = 24), and young (aged 21-39 years, n = 12) subjects were collected. We used two proteomic techniques, two-dimensional differential gel electrophoresis and isobaric tags for relative and absolute quantitation, and we subjected differentially-expressed proteins among age groups to immunohistochemical analyses.
Proteomic analyses showed that the expression of lactadherin, which produces medin, was elevated in aortic media of older-aged individuals. Immunohistochemical and Congo red staining showed that lactadherin and apolipoprotein E were deposited, and that amyloidosis was enhanced in older-aged aortic media. Furthermore, the markers of oxidative damage (8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal) were significantly elevated in aortic media of middle-aged or older-aged individuals. The immunohistochemical expression of anti-oxidant proteins (thioredoxin and extracellular superoxide dismutase) was also high in middle-aged and older-aged groups. Oxidative damage might induce the disruption of smooth muscle cells, resulting in the decrement of α-actin, a highly-expressed protein in smooth muscle cells, and matrix remodeling, in which several proteins associated with extracellular matrix were altered with aging.
Proteomic approaches showed that the elevated expression of lactadherin might contribute to amyloid deposition, enhancement of oxidative stress, induction of antioxidant proteins and matrix remodeling in older-aged aortic media. Geriatr Gerontol Int 2019; 19: 1054-1062.
主要发生在中膜的人血管衰老尚未完全阐明。在这里，我们采用蛋白质组学方法研究了人主动脉中膜与年龄相关的变化，旨在了解血管衰老的分子机制。
收集了来自高龄（70-100 岁，n=25）、中年（49-68 岁，n=24）和青年（21-39 岁，n=12）受试者的冷冻保存的主动脉中膜尸检样本。我们使用了两种蛋白质组学技术，二维差异凝胶电泳和等重同位素标记相对和绝对定量，对不同年龄组之间差异表达的蛋白质进行了免疫组织化学分析。
蛋白质组学分析表明，乳凝集素的表达在高龄个体的主动脉中膜中升高。免疫组织化学和刚果红染色显示，乳凝集素和载脂蛋白 E 沉积，高龄主动脉中膜的淀粉样变性增强。此外，氧化损伤标志物（8-羟基-2'-脱氧鸟苷和 4-羟基-2-壬烯醛）在中年或高龄个体的主动脉中膜中显著升高。抗氧化蛋白（硫氧还蛋白和细胞外超氧化物歧化酶）的免疫组织化学表达在中年和高龄组中也较高。氧化损伤可能诱导平滑肌细胞破坏，导致平滑肌细胞中高度表达的α-肌动蛋白减少，以及基质重塑，其中与年龄相关的几种细胞外基质蛋白发生改变。
蛋白质组学方法表明，乳凝集素的高表达可能导致高龄主动脉中膜的淀粉样沉积、氧化应激增强、抗氧化蛋白诱导和基质重塑。老年学与老年医学国际 2019; 19: 1054-1062。
