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

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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Abstract

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.