Aging and Vascular Diseases, Human Aging Research Institute (HARI), School of Life Science, Jiangxi Key Laboratory of Human Aging, Nanchang University, Nanchang 330031, China.
Int J Mol Sci. 2022 Mar 7;23(5):2879. doi: 10.3390/ijms23052879.
Hyperglycemia is reported to accelerate endothelial cell senescence that contributes to diabetic complications. The underlying mechanism, however, remains elusive. We previously demonstrated as a susceptibility gene for type 2 diabetes mellitus (T2DM) and showed that it was increased in multiple tissues in models with T2DM or metabolic syndrome. This study aimed to investigate the role of AQR in hyperglycemia-induced senescence and its underlying mechanism. Here, we retrieved several datasets of the aging models and found the expression of AQR was increased by high glucose and by aging across species, including (whole-body), rat (cardiac tissues), and monkey (blood). we validated the increased AQR expression in senescent human umbilical vein endothelial cells (HUVECs). When overexpressed, AQR promoted the endothelial cell senescence, confirmed by an increased number of cells stained with senescence-associated beta-galactosidase and upregulation of CDKN1A (P21) as well as the prohibited cellular colony formation and G2/M phase arrest. To explore the mechanism by which AQR regulated the cellular senescence, transcriptomic analyses of HUVECs with the overexpression and knockdown of the AQR were performed. We identified 52 co-expressed genes that were enriched, in the terms of plasminogen activation, innate immunity, immunity, and antiviral defense. Among co-expressed genes, was selected to evaluate its contribution to senescence for its highest strength in the enrichment of the biological process. We demonstrated that the knockdown of PLAU rescued senescence-related phenotypes, endothelial cell activation, and inflammation in models induced by AQR or TNF-α. These findings, for the first time, indicate that AQR/PLAU is a critical signaling axis in the modulation of endothelial cell senescence, revealing a novel link between hyperglycemia and vascular dysfunction. The study may have implications in the prevention of premature vascular aging associated with T2DM.
高血糖被报道可加速内皮细胞衰老，从而导致糖尿病并发症。然而，其潜在机制仍不清楚。我们之前曾将 AQR 鉴定为 2 型糖尿病（T2DM）的易感基因，并在 T2DM 或代谢综合征的模型中发现其在多种组织中均增加。本研究旨在探讨 AQR 在高血糖诱导的衰老中的作用及其潜在机制。在这里，我们检索了衰老模型的多个数据集，发现 AQR 的表达在高糖和跨物种衰老中增加，包括 （全身）、大鼠（心脏组织）和猴子（血液）。我们验证了衰老的人脐静脉内皮细胞（HUVEC）中 AQR 表达增加。当过度表达时，AQR 促进内皮细胞衰老，通过衰老相关β-半乳糖苷酶染色的细胞数量增加以及 CDKN1A（P21）的上调以及细胞集落形成和 G2/M 期阻滞来证实。为了探索 AQR 调节细胞衰老的机制，对过表达和敲低 AQR 的 HUVEC 进行了转录组分析。我们鉴定了 52 个共表达基因，这些基因在纤溶酶原激活、固有免疫、免疫和抗病毒防御等术语中富集。在共表达基因中，选择 PLAU 来评估其对衰老的贡献，因为它在生物过程富集中的强度最高。我们证明，PLAU 的敲低可挽救由 AQR 或 TNF-α诱导的模型中的衰老相关表型、内皮细胞激活和炎症。这些发现首次表明，AQR/PLAU 是调节内皮细胞衰老的关键信号轴，揭示了高血糖与血管功能障碍之间的新联系。该研究可能对预防与 T2DM 相关的过早血管衰老具有重要意义。
Zotero 插件
