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Abstract：
Thoracic aortic dissection (TAD) is a life-threatening vascular disease manifested as intramural bleeding in the medial layers of the thoracic aorta. The key histopathologic feature of TAD is medial degeneration, characterized by depletion of vascular smooth muscle cells (VSMCs) and degradation of extracellular matrix (ECM). MicroRNA, as essential epigenetic regulators, can inhibit the protein expression of target genes without modifying the sequences. This study aimed to elucidate the role and underlying mechanism of miR-20a, a member of the miR-17-92 cluster, in regulating ECM degradation during the pathogenesis of TAD. The expression of the miR-17-92 cluster was significantly increased in synthetic VSMCs derived from TAD lesions compared to contractile VSMCs isolated from normal thoracic aortas. Notably, the expression of miR-20a was increased in VSMCs in response to serum exposure and various stimuli. In TAD lesions, the expression of miR-20a was significantly negatively correlated with that of elastin. Elevated expression of miR-20a was also observed in thoracic aortas of TAD mice induced by β-aminopropionitrile fumarate and angiotensin II. Overexpression of miR-20a via mimic transfection enhanced the growth and invasive capabilities of VSMCs, with no significant impact on their migratory activity or the expression of phenotypic markers (α-SMA, SM22, and OPN). Silencing of miR-20a with inhibitor transfection mitigated the hyperactivation of MMP2 in VSMCs stimulated by PDGF-bb, as evidenced by reduced levels of active-MMP2 and increased levels of pro-MMP2. Subsequently, TIMP2 was identified as a novel target gene of miR-20a. The role of miR-20a in promoting the activation of MMP2 was mediated by the suppression of TIMP2 expression in VSMCs. In addition, the elevated expression of miR-20a was found to be directly driven by Nanog in VSMCs. Collectively, these findings indicate that miR-20a plays a crucial role in maintaining the homeostasis of the thoracic aortic wall during TAD pathogenesis and may represent a potential therapeutic target for TAD.
摘要：
胸主动脉夹层（TAD）是一种危及生命的血管疾病，表现为胸主动脉中层的壁内出血。TAD的关键组织病理学特征是内侧变性，以血管平滑肌细胞（VSMC）耗竭和细胞外基质（ECM）降解为特征。MicroRNA,作为重要的表观遗传调节因子，可以在不改变序列的情况下抑制靶基因的蛋白质表达。本研究旨在阐明miR-20a的作用和潜在机制。miR-17-92簇的成员，在TAD发病过程中调节ECM降解。与从正常胸主动脉分离的收缩性VSMC相比,miR-17-92簇的表达在源自TAD病变的合成VSMC中显著增加。值得注意的是,VSMC中miR-20a的表达在血清暴露和各种刺激下增加.在TAD病变中，miR-20a的表达与弹性蛋白的表达呈显著负相关。在富马酸β-氨基丙腈和血管紧张素II诱导的TAD小鼠的胸主动脉中也观察到miR-20a的表达升高。通过模拟转染过表达miR-20a增强了VSMC的生长和侵袭能力，对它们的迁移活性或表型标记(α-SMA，SM22和OPN）。用抑制剂转染沉默miR-20a减轻了PDGF-bb刺激的VSMC中MMP2的过度激活，如活性MMP2水平降低和pro-MMP2水平升高所证明。随后，TIMP2被鉴定为miR-20a的新靶基因。miR-20a在促进MMP2激活中的作用是通过抑制VSMC中的TIMP2表达来介导的。此外,在VSMC中发现miR-20a的表达升高直接由Nanog驱动.总的来说，这些发现表明miR-20a在TAD发病过程中维持胸主动脉壁的稳态中起着至关重要的作用,并且可能是TAD的潜在治疗靶点.
