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

• Published in: Nature communications Vol. 15; no. 1; pp. 4985 - 17
• Main Authors: Xie, Fei, Liu, Bin, Qiao, Wen, He, Jing-zhen, Cheng, Jie, Wang, Zhao-yang, Hou, Ya-min, Zhang, Xu, Xu, Bo-han, Zhang, Yun, Chen, Yu-guo, Zhang, Ming-xiang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.06.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/2; 42; 42/109; 42/41; 42/47; 42/89; 692/163/2743/137/138; 692/4019/592/2193; 692/699/75/593; 82/80; 96; 96/95; Accumulation; Advanced glycosylation end products; Age; Animals; Apoptosis; Arteriosclerosis; Atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; Calcification; Cdc4 protein; Cell activation; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; F-Box-WD Repeat-Containing Protein 7 - genetics; F-Box-WD Repeat-Containing Protein 7 - metabolism; Glycation End Products, Advanced - metabolism; Humanities and Social Sciences; Humans; Hyperglycemia; Hyperglycemia - genetics; Hyperglycemia - metabolism; Male; Males; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; mRNA; multidisciplinary; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Muscles; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Nuclear Factor 90 Proteins - genetics; Nuclear Factor 90 Proteins - metabolism; Plaque, Atherosclerotic - genetics; Plaque, Atherosclerotic - metabolism; Plaque, Atherosclerotic - pathology; Receptor for Advanced Glycation End Products - genetics; Receptor for Advanced Glycation End Products - metabolism; Science; Science (multidisciplinary); Smooth muscle; Therapeutic targets; Ubiquitin-protein ligase; Ubiquitination; Vascular Calcification - genetics; Vascular Calcification - metabolism; Vascular Calcification - pathology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49315-9

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. The accumulation of AGEs is closely related to the atherosclerotic calcification in diabetic patients. Here, the authors find that VSMC NF90 knockout attenuates diabetic atherosclerotic calcification by mediating the metabolic imbalance of AGEs.