2. Academic Validation
  3. FAM3A reshapes VSMC fate specification in abdominal aortic aneurysm by regulating KLF4 ubiquitination

FAM3A reshapes VSMC fate specification in abdominal aortic aneurysm by regulating KLF4 ubiquitination

  • Nat Commun. 2023 Sep 2;14(1):5360. doi: 10.1038/s41467-023-41177-x.
Chuxiang Lei # 1,  Haoxuan Kan # 1,  Xiangyu Xian # 1,  Wenlin Chen 1,  Wenxuan Xiang 1,  Xiaohong Song 1 2,  Jianqiang Wu 1 2,  Dan Yang 3,  Yuehong Zheng 4
Affiliations

Affiliations

  • 1 Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng District, Beijing, 100730, China.
  • 2 State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng District, Beijing, 100730, China.
  • 3 Department of Computational Biology and Bioinformatics, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Haidian District, Beijing, 100193, China. dyang0226@163.com.
  • 4 Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng District, Beijing, 100730, China. zhengyuehong2022@outlook.com.
  • # Contributed equally.
PMID: 37660071 DOI: 10.1038/s41467-023-41177-x
Abstract

Reprogramming of vascular smooth muscle cell (VSMC) differentiation plays an essential role in abdominal aortic aneurysm (AAA). However, the underlying mechanisms are still unclear. We explore the expression of FAM3A, a newly identified metabolic cytokine, and whether and how FAM3A regulates VSMC differentiation in AAA. We discover that FAM3A is decreased in the aortas and plasma in AAA patients and murine models. Overexpression or supplementation of FAM3A significantly attenuate the AAA formation, manifested by maintenance of the well-differentiated VSMC status and inhibition of VSMC transformation toward macrophage-, chondrocyte-, osteogenic-, mesenchymal-, and fibroblast-like cell subpopulations. Importantly, FAM3A induces KLF4 ubiquitination and reduces its phosphorylation and nuclear localization. Here, we report FAM3A as a VSMC fate-shaping regulator in AAA and reveal the underlying mechanism associated with KLF4 ubiquitination and stability, which may lead to the development of strategies based on FAM3A to restore VSMC homeostasis in AAA.

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