ALAS2 overexpression alleviates oxidative stress-induced ferroptosis in aortic aneurysms via GATA1 activation

Yunjun He; Xiaohui Wang; Donglin Li; Qianqian Zhu; Yilang Xiang; Yangyan He; Hongkun Zhang

doi:10.21037/jtd-24-370

ALAS2 overexpression alleviates oxidative stress-induced ferroptosis in aortic aneurysms via GATA1 activation

J Thorac Dis. 2024 Apr 30;16(4):2510-2527. doi: 10.21037/jtd-24-370. Epub 2024 Apr 29.

Authors

Yunjun He^#¹, Xiaohui Wang^#¹, Donglin Li¹, Qianqian Zhu¹, Yilang Xiang¹, Yangyan He¹, Hongkun Zhang¹

Affiliation

¹ Department of the Vascular Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

^# Contributed equally.

Abstract

Background: Aortic aneurysm, characterized by abnormal dilation of the aorta, poses significant health risks. This study aims to investigate the interaction between 5-aminolevulinate synthase 2 (ALAS2) and GATA-binding protein 1 (GATA1) in ferroptosis and oxidative stress responses in aortic aneurysm.

Methods: A weighted gene co-expression network analysis (WGCNA) was performed on the differentially expressed genes (DEGs) within the GSE9106 dataset to identify the key module. Subsequently, protein-protein interaction (PPI) network analysis was performed on the key module. Mouse aortic vascular smooth muscle cells (MOVAS) were treated with hydrogen peroxide (H₂O₂) to induce oxidative stress, and ferroptosis inducers and inhibitors were added to evaluate their effects on iron content and oxidative stress markers. Through a series of in vitro cellular experiments, we assessed cell viability, expression levels of GATA1 and iron mutation-associated proteins, as well as cellular phenotypes such as inflammatory responses and apoptosis rates.

Results: Three candidate genes (ALAS2, GYPA, and GYPB) were upregulated in the thoracic aortic aneurysm (TAA) samples of the GSE9106 dataset. The H₂O₂ treatment increased the MOVAS cells' iron content and oxidative stress, upregulated ALAS2 protein levels, and decreased the ferroptosis-related protein levels. ALAS2 overexpression reversed H₂O₂-induced apoptosis and increased the inflammatory cytokine levels. Additionally, the knockdown of GATA1 partially reversed the protective mechanism of overexpressed ALAS2 on H₂O₂-induced ferroptosis.

Conclusions: ALAS2 overexpression reduced H₂O₂-induced oxidative damage and iron-induced apoptosis in MOVAS cells, and GATA1 knockdown partially reversed this protective effect. These findings suggested that the ALAS2 and GATA1 regulatory pathways may be potential therapeutic targets in aortic aneurysms.

Keywords: 5-aminolevulinate synthase 2 (ALAS2); GATA binding protein 1 (GATA1); aortic aneurysms; ferroptosis.