揭示GATA4在内皮细胞衰老和动脉粥样硬化发展中的作用

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis Pub Date : 2025-04-03 DOI:10.1016/j.atherosclerosis.2025.119183

Chun-Min Kang , Jing-Jing Zhao , Xi-Xi Xie , Ke-Wei Yu , Bai-Cong Lai , Yun-Xiu Wang , Ting Ting Li , Pei-Feng Ke , Xian-Zhang Huang

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引用次数: 0

摘要

背景和目的细胞衰老与动脉粥样硬化的发生和发展密切相关。然而，其机制尚不清楚。GATA4是人类成纤维细胞衰老的经典调节因子。本研究旨在确定GATA4在内皮细胞（EC）衰老和动脉粥样硬化发展中的作用及其作用机制。方法用H2O2诱导人脐静脉原代内皮细胞衰老。在老年人（65岁）和老年小鼠（24个月）的动脉组织内皮祖细胞（EPCs）、内皮祖细胞中检测GATA4水平。利用带有EC选择性Tie1启动子的腺相关病毒（一种EC特异性基因转导系统），研究了GATA4在ApoE−/−小鼠EC衰老和动脉粥样硬化发展中的作用。采用RT-qPCR、Western blot、ChIP-PCR、ELISA等方法进一步探讨GATA4在EC衰老和动脉粥样硬化发生中的作用机制。结果H2O2和EPCs诱导的老年EC衰老中gata4蛋白水平升高。此外，老年人和老年小鼠动脉组织ECs中GATA4蛋白水平升高，并与动脉粥样硬化斑块的进展密切相关。敲低GATA4可减少EC衰老、功能障碍和单核细胞粘附。在机制上，我们发现GATA4激活NFκB2转录并诱导衰老相关分泌表型（SASP）表达（IL-6、IL-8、CXCL1、CXCL3、ICAM-1）。ApoE−/−小鼠的体内实验表明，ECs中GATA4过表达导致SASP表达升高、血管衰老、动脉粥样硬化斑块形成和心功能受损。综上所述，我们的研究结果表明，EC GATA4水平升高通过GATA4- nf - κ b2 - sasp途径促进动脉粥样硬化的进展，提示动脉粥样硬化相关疾病的潜在治疗靶点。

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Unveiling the role of GATA4 in endothelial cell senescence and atherosclerosis development

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Unveiling the role of GATA4 in endothelial cell senescence and atherosclerosis development

Background and aims

Cellular senescence is intimately linked to atherosclerosis development and progression. However, the mechanism is not well known. GATA4 is a classical regulator in human fibroblast senescence. This study aimed to determine the role of GATA4 in endothelial cell (EC) senescence and atherosclerosis development and the mechanisms by which it acts.

Methods

Senescence ECs were induced using H₂O₂ by isolating human primary umbilical vein ECs from umbilical veins. The level of GATA4 was examined in endothelial progenitor cells (EPCs), ECs of arterial tissue from older individuals (>65 years), and aged mice (>24 months). Adeno-associated virus with EC-selective Tie1 promoter, an EC-specific gene transduction system, was used to explore the role of GATA4 in EC senescence and atherosclerosis development in ApoE^−/− mice. RT-qPCR, Western blot, ChIP-PCR, and ELISA were conducted to further explore the mechanism of GATA4 in EC senescence and atherosclerosis development.

Results

GATA4 protein levels are elevated in EC senescence induced by H₂O₂ and EPCs in older individuals. Additionally, GATA4 protein levels are increased in the ECs of arterial tissue from older individuals and aged mice and are strongly correlated with the progression of atherosclerosis plaques. Knockdown of GATA4 decreased EC senescence, dysfunction, and monocyte adhesion. Mechanistically, we found that GATA4 activates NFκB2 transcription and induces senescence-associated secretory phenotype (SASP) expression (IL-6, IL-8, CXCL1, CXCL3, ICAM-1). In vivo experiments on ApoE^−/− mice demonstrated that GATA4 overexpression in ECs contributes to higher SASP expression, vascular senescence, atherosclerotic plaque formation, and impaired cardiac function.

Conclusions

Taken together, our findings indicate that elevated EC GATA4 levels contribute to the progression of atherosclerosis through the GATA4-NFκB2-SASP pathway, suggesting potential therapeutic targets for atherosclerosis-related diseases.

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来源期刊

Atherosclerosis 医学-外周血管病

CiteScore

9.80

自引率

3.80%

发文量

1269

审稿时长

36 days

期刊介绍： Atherosclerosis has an open access mirror journal Atherosclerosis: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review. Atherosclerosis brings together, from all sources, papers concerned with investigation on atherosclerosis, its risk factors and clinical manifestations. Atherosclerosis covers basic and translational, clinical and population research approaches to arterial and vascular biology and disease, as well as their risk factors including: disturbances of lipid and lipoprotein metabolism, diabetes and hypertension, thrombosis, and inflammation. The Editors are interested in original or review papers dealing with the pathogenesis, environmental, genetic and epigenetic basis, diagnosis or treatment of atherosclerosis and related diseases as well as their risk factors.