Cellular senescence is one of the most significant factors involved in aging and age-related diseases. Senescence of vascular smooth muscle cells (VSMCs) adversely affects the function of the cardiovascular system and contributes to the development of atherosclerosis, hypertension, and other cardiovascular diseases. Glucagon-like peptide-1 (GLP-1) is an important incretin hormone involved in insulin release and vascular tone. GLP-1 is quickly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4). Omarigliptin is a new DPP-4 inhibitor that has demonstrated anti-inflammatory and antioxidative stress properties. In the present study, we investigated the effects of the selective DPP-4 inhibitor omarigliptin (OMG) on VSMCs exposed to insult from tumor necrosis factor-α (TNF-α), one of the main inflammatory signaling molecules involved in cellular senescence. We found that OMG could suppress TNF-α-induced expression of pro-inflammatory cytokines (interleukin-1β (IL-1β), IL-6, and IL-8) and inhibit oxidative stress by reducing the production of H₂O₂ and protein carbonyl. OMG ameliorated the increase in senescence-associated β-galactosidase (SA-β-gal) and telomerase activity induced by TNF-α. The plasminogen activator inhibitor-1 (PAI-1)/p53/p21 pathway is a key inducer of cellular senescence. OMG ameliorated the acetylation of p53 at lysine 382 (K382) and subsequent activation of p21 via inhibition of PAI-1. Importantly, our experiments revealed that blockage of silent information-regulator 1 (SIRT1) abolished the inhibitory effects of OMG on p53 acetylation, SA-β-gal activity, and telomerase activity in VSMCs. These results suggest that OMG may have the potential to delay or prevent the progression of age-related cardiovascular diseases by modulating the activity of SIRT1.

中文翻译：

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奥马列汀可预防大鼠主动脉血管平滑肌细胞中 TNF-α 诱导的细胞衰老

细胞衰老是与衰老和年龄相关疾病相关的最重要因素之一。血管平滑肌细胞 (VSMCs) 的衰老对心血管系统的功能产生不利影响，并导致动脉粥样硬化、高血压和其他心血管疾病的发展。胰高血糖素样肽-1 (GLP-1) 是一种重要的肠促胰岛素激素，参与胰岛素释放和血管张力。GLP-1 被二肽基肽酶 4 (DPP-4) 酶快速降解。Omarigliptin 是一种新型 DPP-4 抑制剂，具有抗炎和抗氧化应激特性。在本研究中，我们研究了选择性 DPP-4 抑制剂奥格列汀 (OMG) 对暴露于肿瘤坏死因子-α (TNF-α) 损伤的 VSMC 的影响，参与细胞衰老的主要炎症信号分子之一。我们发现 OMG 可以抑制 TNF-α 诱导的促炎细胞因子（白介素 1β (IL-1β)、IL-6 和 IL-8）的表达，并通过减少 H 的产生来抑制氧化应激。₂ O ₂和蛋白质羰基。OMG 改善了 TNF-α 诱导的衰老相关 β-半乳糖苷酶 (SA-β-gal) 和端粒酶活性的增加。纤溶酶原激活物抑制剂-1 (PAI-1)/p53/p21 通路是细胞衰老的关键诱导因子。OMG 通过抑制 PAI-1 改善了 p53 在赖氨酸 382 (K382) 的乙酰化和随后的 p21 活化。重要的是，我们的实验表明，沉默信息调节因子 1 (SIRT1) 的阻断消除了 OMG 对 VSMC 中 p53 乙酰化、SA-β-gal 活性和端粒酶活性的抑制作用。这些结果表明，OMG 可能通过调节 SIRT1 的活性来延缓或预防与年龄相关的心血管疾病的进展。