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

Chuxiang Lei, Haoxuan Kan, Xiangyu Xian, Wenlin Chen, Wenxuan Xiang, Xiaohong Song, Jianqiang Wu, Dan Yang () and Yuehong Zheng ()
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Chuxiang Lei: Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng District
Haoxuan Kan: Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng District
Xiangyu Xian: Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng District
Wenlin Chen: Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng District
Wenxuan Xiang: Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng District
Xiaohong Song: Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng District
Jianqiang Wu: Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng District
Dan Yang: Chinese Academy of Medical Sciences and Peking Union Medical College, Haidian District
Yuehong Zheng: Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng District

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41177-x

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