Kang Chun-Min, Zhao Jing-Jing, Xie Xi-Xi, Yu Ke-Wei, Lai Bai-Cong, Wang Yun-Xiu, Li Ting Ting, Ke Pei-Feng, Huang Xian-Zhang
The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510120, China; Department of Laboratory Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, 510120, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, Guangdong, 510120, China.
Department of Laboratory Medicine, Nanfang Hospital Affiliated to Southern Medical University, Guangdong, 510515, China.
Atherosclerosis. 2025 May;404:119183. doi: 10.1016/j.atherosclerosis.2025.119183. Epub 2025 Apr 3.
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.
Senescence ECs were induced using HO 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.
GATA4 protein levels are elevated in EC senescence induced by HO 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.
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.
细胞衰老与动脉粥样硬化的发生发展密切相关。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生中的作用及其作用机制。
通过从脐静脉分离人原代脐静脉内皮细胞，用HO诱导衰老内皮细胞。检测内皮祖细胞（EPC）、老年个体（>65岁）动脉组织内皮细胞和老年小鼠（>24个月）中GATA4的水平。使用具有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，来探讨GATA4在ApoE小鼠内皮细胞衰老和动脉粥样硬化发生中的作用。进行RT-qPCR、蛋白质印迹、染色质免疫沉淀PCR和酶联免疫吸附测定，以进一步探讨GATA4在内皮细胞衰老和动脉粥样硬化发生中的机制。
HO诱导的内皮细胞衰老以及老年个体的EPC中GATA4蛋白水平升高。此外，老年个体和老年小鼠动脉组织的内皮细胞中GATA4蛋白水平增加，且与动脉粥样硬化斑块的进展密切相关。敲低GATA4可降低内皮细胞衰老、功能障碍和单核细胞黏附。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）。对ApoE小鼠的体内实验表明，内皮细胞中GATA4过表达导致更高的SASP表达、血管衰老、动脉粥样硬化斑块形成和心脏功能受损。
综上所述，我们的研究结果表明，内皮细胞中GATA4水平升高通过GATA4-NFκB2-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。
