Smooth muscle NF90 deficiency ameliorates diabetic atherosclerotic calcification in male mice via FBXW7-AGER1-AGEs axis

Fei Xie, Bin Liu, Wen Qiao, Jing-zhen He, Jie Cheng, Zhao-yang Wang, Ya-min Hou, Xu Zhang, Bo-han Xu, Yun Zhang (), Yu-guo Chen () and Ming-xiang Zhang ()
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Fei Xie: Qilu Hospital of Shandong University
Bin Liu: Qilu Hospital of Shandong University
Wen Qiao: Qilu Hospital of Shandong University
Jing-zhen He: Qilu Hospital of Shandong University
Jie Cheng: Qilu Hospital of Shandong University
Zhao-yang Wang: Shandong University
Ya-min Hou: Qilu Hospital of Shandong University
Xu Zhang: Qilu Hospital of Shandong University
Bo-han Xu: Qilu Hospital of Shandong University
Yun Zhang: Qilu Hospital of Shandong University
Yu-guo Chen: Qilu Hospital of Shandong University
Ming-xiang Zhang: Qilu Hospital of Shandong University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Hyperglycemia accelerates calcification of atherosclerotic plaques in diabetic patients, and the accumulation of advanced glycation end products (AGEs) is closely related to the atherosclerotic calcification. Here, we show that hyperglycemia-mediated AGEs markedly increase vascular smooth muscle cells (VSMCs) NF90/110 activation in male diabetic patients with atherosclerotic calcified samples. VSMC-specific NF90/110 knockout in male mice decreases obviously AGEs-induced atherosclerotic calcification, along with the inhibitions of VSMC phenotypic changes to osteoblast-like cells, apoptosis, and matrix vesicle release. Mechanistically, AGEs increase the activity of NF90, which then enhances ubiquitination and degradation of AGE receptor 1 (AGER1) by stabilizing the mRNA of E3 ubiquitin ligase FBXW7, thus causing the accumulation of more AGEs and atherosclerotic calcification. Collectively, our study demonstrates the effects of VSMC NF90 in mediating the metabolic imbalance of AGEs to accelerate diabetic atherosclerotic calcification. Therefore, inhibition of VSMC NF90 may be a potential therapeutic target for diabetic atherosclerotic calcification.

Date: 2024
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DOI: 10.1038/s41467-024-49315-9

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