1 Histology and Embryology Section, University of Verona Medical School, Italy.
2 Department of Surgical Sciences, University of Verona Medical School, Italy.
Eur J Prev Cardiol. 2018 Jun;25(1_suppl):42-50. doi: 10.1177/2047487318759119.
Background Sporadic non-syndromic thoracic aortic aneurysms (SNSTAAs) are less well understood than familial non-syndromic or syndromic ones. The study aimed at defining the peculiar morphologic and molecular changes occurring in the media layer of SNSTAAs. Design This study was based on a single centre design. Methods Media layer samples taken from seven carefully selected SNSTAAs and seven reference patients (controls) were investigated via quantitative polymerase chain reaction, proteomics-bioinformatics, immunoblotting, quantitative histology, and immunohistochemistry/immunofluorescence. Results In SNSTAAs media, aortic smooth muscle cells numbers were halved due to an apoptotic process coupled with a negligible cell proliferation. Cystathionine γ-lyase was diffusely up-regulated. Surviving aortic smooth muscle cells exhibited diverging phenotypes: in inner- and outer-media contractile cells prevailed, having higher contents of smooth-muscle-α-actin holoprotein (45-kDa) and of caspase-3-cleaved smooth-muscle-α-actin 25-kDa fragments; in mid-media, aortic smooth muscle cells exhibited a synthetic/secretor phenotype, down-regulating vimentin, but up-regulating glial fibrillary acidic protein, trans-Golgi network 46 protein, Jagged1 (172-kDa) holoprotein, and Jagged1's receptor Notch1. Extracellular soluble Jagged1 (42-kDa) fragments accumulated. Conclusions In SNSTAAs, there is a relentless aortic smooth muscle cells attrition caused by the up-regulated cystathionine γ-lyase. In mid-media, synthetic/secretor aortic smooth muscle cells intensify Jagged1/NOTCH1 signalling in the attempt to counterbalance the weakened aortic wall, due to aortic smooth muscle cells net loss and mechanical stress. Synthetic/secretor aortic smooth muscle cells are apoptosis-prone, and the accruing thrombin-cleaved Jagged1 fragments counteract the otherwise useful effects of Jagged1/NOTCH1 signalling, thus hampering tissue homeostasis/remodelling, and aortic smooth muscle cells adhesion, differentiation, and migration.
散发性非综合征性胸主动脉瘤（SNSTAAs）的了解不如家族性非综合征性或综合征性胸主动脉瘤。本研究旨在确定发生在 SNSTAAs 中膜层的特殊形态和分子变化。
本研究基于单中心设计。
通过定量聚合酶链反应、蛋白质组学-生物信息学、免疫印迹、定量组织学和免疫组织化学/免疫荧光，对从 7 例精心挑选的 SNSTAAs 和 7 例参考患者（对照）中获得的中膜层样本进行了研究。
在 SNSTAAs 中膜层，由于凋亡过程和微不足道的细胞增殖，平滑肌细胞数量减少了一半。胱硫醚γ-裂解酶广泛上调。存活的平滑肌细胞表现出不同的表型：在中膜内层和外层，收缩型细胞占主导地位，平滑肌-α-肌动蛋白全蛋白（45 kDa）和半胱天冬酶-3 切割的平滑肌-α-肌动蛋白 25 kDa 片段含量较高；在中膜层，平滑肌细胞表现出合成/分泌表型，下调波形蛋白，但上调神经胶质纤维酸性蛋白、跨高尔基网络 46 蛋白、Jagged1（172 kDa）全蛋白和 Jagged1 的受体 Notch1。细胞外可溶性 Jagged1（42 kDa）片段积累。
在 SNSTAAs 中，由于胱硫醚γ-裂解酶的上调，平滑肌细胞不断损耗。在中膜层，合成/分泌型平滑肌细胞加强 Jagged1/NOTCH1 信号转导，试图抵消由于平滑肌细胞净损失和机械应力导致的主动脉壁减弱。合成/分泌型平滑肌细胞易发生凋亡，积累的凝血酶切割的 Jagged1 片段抵消了 Jagged1/NOTCH1 信号转导的有益作用，从而阻碍了组织内稳态/重塑以及平滑肌细胞的黏附、分化和迁移。
