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

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 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.

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.

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.