The TGF-β1-oxidative stress axis underlies accelerated senescence of endothelial cells exposed to serum from hypertensive patients

IF 6.5 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development Pub Date : 2026-02-01 Epub Date: 2025-11-26 DOI:10.1016/j.mad.2025.112128

Paweł Uruski , Justyna Mikuła-Pietrasik , Andrzej Tykarski , Krzysztof Książek

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引用次数: 0

Abstract

Background

There is a bidirectional link between hypertension (HT) and cellular senescence of endothelial cells (ECs). However, the mechanisms underlying EC senescence in patients with HT are not yet fully understood.

Methods and Results

We analyzed serum from 71 patients with primary HT and compared it to serum from 25 healthy donors to assess its effects on EC biology, including biomarkers, signaling pathways, and cellular senescence effectors. Our findings revealed that exposing ECs to serum from HT patients (20 % for 72 h) impaired cell viability while enhancing proliferation, migration, and tubulogenesis. This effect is accompanied by increased expression of HIF-1α. Additionally, HT serum potentiated the expression of the senescence marker SA-β-Gal, shortened telomeres, and up-regulated cell-cycle inhibitors p16, p21, and p53. Regarding the signaling pathways, HT serum activated ERK1/2, p38 MAPK, AP-1/c-jun, and Notch1. Indices of oxidative stress in ECs treated with HT serum also increased, as indicated by elevated production of superoxides, activation of antioxidants (SOD, CAT), and accumulation of oxidized DNA, proteins, and lipids. Furthermore, mitochondria in these cells displayed decreased inner membrane potential and increased biogenesis, likely due to enhanced activity of PGC-1α. The activity of respiratory chain enzymes, including cytochrome c oxidase and NADH dehydrogenase, was also elevated. When HT serum-treated ECs were pre-incubated with the ROS scavenger PBN, the activity of SA-β-Gal decreased. A similar reduction in SA-β-Gal activity was observed when HT serum, which contained elevated levels of TGF-β1, was pre-incubated with a TGF-β1-neutralizing antibody. Importantly, exogenous TGF-β1, administered at a dose corresponding to its concentration in HT serum, induced senescence in ECs.

Conclusions

Our results indicate that serum from HT patients promotes senescence in ECs through mechanisms related to TGF-β1 and oxidative stress signaling.

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TGF-β1-氧化应激轴是高血压患者血清内皮细胞加速衰老的基础。

背景：高血压（HT）与内皮细胞（ECs）细胞衰老之间存在双向联系。然而，HT患者EC衰老的机制尚不完全清楚。方法和结果：我们分析了71例原发性HT患者的血清，并将其与25例健康供者的血清进行比较，以评估其对EC生物学的影响，包括生物标志物、信号通路和细胞衰老效应物。我们的研究结果显示，将ECs暴露于HT患者的血清（20%，72小时）会损害细胞活力，同时增强增殖、迁移和小管形成。这种作用伴随着HIF-1α表达的增加。此外，HT血清增强了衰老标志物SA-β-Gal、端粒缩短和细胞周期抑制剂p16、p21和p53的表达。在信号通路方面，HT血清激活了ERK1/2、p38 MAPK、AP-1/c-jun和Notch1。经HT血清处理的ECs氧化应激指标也有所增加，如超氧化物的产生、抗氧化剂（SOD、CAT）的激活以及氧化DNA、蛋白质和脂质的积累。此外，这些细胞中的线粒体表现出内膜电位下降和生物发生增加，可能是由于PGC-1α活性增强。呼吸链酶，包括细胞色素c氧化酶和NADH脱氢酶的活性也升高。当HT血清处理的ECs与ROS清除剂PBN预孵育时，SA-β-Gal活性降低。将含有TGF-β1水平升高的HT血清与TGF-β1中和抗体预孵育后，观察到SA-β-Gal活性的类似降低。重要的是，外源性TGF-β1，给药剂量与其在HT血清中的浓度相对应，可诱导内皮细胞衰老。结论：我们的研究结果表明HT患者的血清通过TGF-β1和氧化应激信号相关的机制促进ECs衰老。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Mechanisms of Ageing and Development 医学-老年医学

CiteScore

11.10

自引率

1.90%

发文量

审稿时长

32 days

期刊介绍： Mechanisms of Ageing and Development is a multidisciplinary journal aimed at revealing the molecular, biochemical and biological mechanisms that underlie the processes of aging and development in various species as well as of age-associated diseases. Emphasis is placed on investigations that delineate the contribution of macromolecular damage and cytotoxicity, genetic programs, epigenetics and genetic instability, mitochondrial function, alterations of metabolism and innovative anti-aging approaches. For all of the mentioned studies it is necessary to address the underlying mechanisms. Mechanisms of Ageing and Development publishes original research, review and mini-review articles. The journal also publishes Special Issues that focus on emerging research areas. Special issues may include all types of articles following peered review. Proposals should be sent directly to the Editor-in-Chief.