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Int J Biol Sci 2022; 18(15):5978-5993. doi:10.7150/ijbs.74864 This issue Cite

Research Paper

SRC-3 deficiency prevents atherosclerosis development by decreasing endothelial ICAM-1 expression to attenuate macrophage recruitment

Wenbo Chen1, Wuyang Zheng1, Shixiao Liu1, Qiang Su2, Kangxi Ding1, Ziguan Zhang1, Ping Luo1, Yong Zhang3, Jianming Xu4, Chundong Yu3✉, Weihua Li1✉, Zhengrong Huang1✉

1. Department of Cardiology, Xiamen Key Laboratory of Cardiac Electrophysiology, Xiamen Institute of Cardiovascular Diseases, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
2. Key Laboratory of Prevention and treatment of cardiovascular and cerebrovascular diseases of Ministry of Education, Jiangxi Provincial Clinical Research Center for Vascular Anomalies, Gannan Medical University, Ganzhou, Jiangxi, China.
3. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China.
4. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.

✉ Corresponding authors: Zhengrong Huang, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China. E-mail huangzhengrongedu.cn or Weihua Li, The First Affiliated Hospital of Xiamen University, Scho More

Citation:
Chen W, Zheng W, Liu S, Su Q, Ding K, Zhang Z, Luo P, Zhang Y, Xu J, Yu C, Li W, Huang Z. SRC-3 deficiency prevents atherosclerosis development by decreasing endothelial ICAM-1 expression to attenuate macrophage recruitment. Int J Biol Sci 2022; 18(15):5978-5993. doi:10.7150/ijbs.74864. https://www.ijbs.com/v18p5978.htm
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Abstract

Graphic abstract

Steroid receptor coactivator 3 (SRC-3) is a member of the p160 SRC family. This factor can interact with multiple nuclear hormone receptors and transcription factors to regulate the expression of their target genes. Although many physiological roles of SRC-3 have been revealed, its role in atherosclerosis is not clear. In this study, we found that SRC-3-/-ApoE-/- mice have reduced atherosclerotic lesions and necrotic areas in their aortas and aortic roots compared with SRC-3+/+ApoE-/- mice after Western diet (WD) feeding for 12 weeks. RNA-Seq and Western blot analyses of the aorta revealed that SRC-3 was required for maintaining the expression of ICAM-1, which was required for macrophage recruitment and atherosclerosis development. siRNA-mediated knockdown of SRC-3 in endothelial cells significantly reduced WD-induced atherosclerotic plaque formation. Additionally, treatment of ApoE-/- mice with SRC-3 inhibitor bufalin prevented atherosclerotic plaque development. SRC-3 deficiency reduced aortic macrophage recruitment. Accordingly, ICAM-1 expression was markedly decreased in the aortas of SRC-3-/-ApoE-/- mice and ApoE-/- mice with endothelial SRC-3 knockdown mediated by AAV9-shSRC-3 virus. Mechanistically, SRC-3 coactivated NF-κB p65 to increase ICAM-1 transcription in endothelial cells. Collectively, these findings demonstrate that inhibiting SRC-3 ameliorates atherosclerosis development, at least in part through suppressing endothelial activation by decreasing endothelial ICAM-1 expression via reducing NF-κB signaling.

Keywords: SRC-3, endothelial cell, ICAM-1, bufalin, NF-κB signaling

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APA
Chen, W., Zheng, W., Liu, S., Su, Q., Ding, K., Zhang, Z., Luo, P., Zhang, Y., Xu, J., Yu, C., Li, W., Huang, Z. (2022). SRC-3 deficiency prevents atherosclerosis development by decreasing endothelial ICAM-1 expression to attenuate macrophage recruitment. International Journal of Biological Sciences, 18(15), 5978-5993. https://doi.org/10.7150/ijbs.74864.

ACS
Chen, W.; Zheng, W.; Liu, S.; Su, Q.; Ding, K.; Zhang, Z.; Luo, P.; Zhang, Y.; Xu, J.; Yu, C.; Li, W.; Huang, Z. SRC-3 deficiency prevents atherosclerosis development by decreasing endothelial ICAM-1 expression to attenuate macrophage recruitment. Int. J. Biol. Sci. 2022, 18 (15), 5978-5993. DOI: 10.7150/ijbs.74864.

NLM
Chen W, Zheng W, Liu S, Su Q, Ding K, Zhang Z, Luo P, Zhang Y, Xu J, Yu C, Li W, Huang Z. SRC-3 deficiency prevents atherosclerosis development by decreasing endothelial ICAM-1 expression to attenuate macrophage recruitment. Int J Biol Sci 2022; 18(15):5978-5993. doi:10.7150/ijbs.74864. https://www.ijbs.com/v18p5978.htm

CSE
Chen W, Zheng W, Liu S, Su Q, Ding K, Zhang Z, Luo P, Zhang Y, Xu J, Yu C, Li W, Huang Z. 2022. SRC-3 deficiency prevents atherosclerosis development by decreasing endothelial ICAM-1 expression to attenuate macrophage recruitment. Int J Biol Sci. 18(15):5978-5993.

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