The Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China.
Nat Commun. 2024 Jun 11;15(1):4985. 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.
高血糖加速糖尿病患者动脉粥样硬化斑块的钙化，而晚期糖基化终产物（AGEs）的积累与动脉粥样硬化钙化密切相关。在这里，我们显示高血糖介导的 AGEs 显著增加了男性糖尿病伴动脉粥样硬化钙化样本中血管平滑肌细胞（VSMCs）NF90/110 的激活。在雄性小鼠中，VSMC 特异性 NF90/110 敲除明显减少了 AGEs 诱导的动脉粥样硬化钙化，同时抑制了 VSMC 向成骨样细胞、凋亡和基质小泡释放的表型变化。在机制上，AGEs 增加 NF90 的活性，然后通过稳定 E3 泛素连接酶 FBXW7 的 mRNA 增强 AGE 受体 1（AGER1）的泛素化和降解，从而导致更多的 AGEs 积累和动脉粥样硬化钙化。总之，我们的研究表明 VSMC NF90 在介导 AGEs 的代谢失衡以加速糖尿病性动脉粥样硬化钙化方面的作用。因此，抑制 VSMC NF90 可能是治疗糖尿病性动脉粥样硬化钙化的一个潜在靶点。
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