2. Academic Validation
  3. Endothelial Gsα deficiency promotes ferroptosis and exacerbates atherosclerosis in apolipoprotein E-deficient mice via the inhibition of NRF2 signaling

Endothelial Gsα deficiency promotes ferroptosis and exacerbates atherosclerosis in apolipoprotein E-deficient mice via the inhibition of NRF2 signaling

  • Acta Pharmacol Sin. 2025 Jan 13. doi: 10.1038/s41401-024-01446-x.
Li-Fan He # 1 2,  Lei Wang # 1 2,  Jing-Wei Li 1,  Xiao Xiong 1,  Xiao-Lin Yue 1,  Pei-Dong Yuan 1,  Han-Lin Lu 1,  Jian-Gang Gao 3,  Fang-Pu Yu 1,  Min Chen 4,  Lee S Weinstein 4,  Jian-Min Yang 1,  Cheng Zhang 1,  Xiaoteng Qin 5,  Wencheng Zhang 6
Affiliations

Affiliations

  • 1 State Key Laboratory for Innovation and Transformation of Luobing Theory; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, 250012, China.
  • 2 Department of Critical Care Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
  • 3 School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, 250013, China.
  • 4 Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20814, USA.
  • 5 State Key Laboratory for Innovation and Transformation of Luobing Theory; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, 250012, China. qinxt1990@163.com.
  • 6 State Key Laboratory for Innovation and Transformation of Luobing Theory; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, 250012, China. zhangwencheng@sdu.edu.cn.
  • # Contributed equally.
PMID: 39806063 DOI: 10.1038/s41401-024-01446-x
Abstract

The importance of Ferroptosis in the occurrence and progression of atherosclerosis is gradually being recognized. The stimulatory G protein α subunit (Gsα) plays a crucial role in the physiology of endothelial cells (ECs). Our previous study showed that endothelial Gsα could regulate angiogenesis and preserve endothelial permeability. In this study, we investigated whether endothelial Gsα contributed to atherosclerosis through Ferroptosis and oxidative stress. We generated endothelial Gsα-specific knockout mice in Apolipoprotein E-deficient (apoE-/-) background (apoE-/-GsαECKO), and found that the mice exhibited aggravated atherosclerotic lesions and signs of Ferroptosis compared with their wild-type littermates (apoE-/-Gsαfl/fl). In human aortic endothelial cells (HAECs), overexpression of Gsα reduced lipid peroxidation and Ferroptosis, whereas Gsα knockdown exacerbated oxidative stress and Ferroptosis. Further, Gsα overexpression in HAECs increased the expression of antioxidant genes nuclear factor erythroid 2-related 2 (NRF2) and its downstream genes. Gsα regulated the expression of NRF2 through CCCTC-binding factor (CTCF). In conclusion, this study has revealed that Gsα acts as a defense factor against endothelial Ferroptosis and is a potential target for the treatment of atherosclerosis and associated ischemic heart disease. A model depicting the increase in the endothelial Gsα protein level in response to atherosclerotic stimuli. Gsα regulates NRF2 expression through cAMP/Epac/CTCF-mediated transcription and inhibits Ferroptosis. Endothelial Gsα deficiency alleviates antioxidative stress and exacerbates atherosclerosis.

Keywords

Gsα; NRF2; atherosclerosis; endothelial cells; ferroptosis.

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