Nephrology and Dialysis Unit, San Luca Hospital, 55100 Lucca, Italy.
Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy.
Int J Mol Sci. 2023 Feb 3;24(3):2960. doi: 10.3390/ijms24032960.
The mechanisms by which hyperuricemia induces vascular dysfunction and contributes to cardiovascular disease are still debated. Phenotypic transition is a property of vascular smooth muscle cells (VSMCs) involved in organ damage. The aim of this study was to investigate the effects of uric acid (UA) on changes in the VSMC cytoskeleton, cell migration and the signals involved in these processes. MOVAS, a mouse VSMC line, was incubated with 6, 9 and 12 mg/dL of UA, angiotensin receptor blockers (ARBs), proteasome and MEK-inhibitors. Migration property was assessed in a micro-chemotaxis chamber and by phalloidin staining. Changes in cytoskeleton proteins (Smoothelin B (SMTB), alpha-Smooth Muscle Actin (αSMA), Smooth Muscle 22 Alpha (SM22α)), Atrogin-1 and MAPK activation were determined by Western blot, immunostaining and quantitative reverse transcription PCR. UA exposition modified SMT, αSMA and SM22α levels ( < 0.05) and significantly upregulated Atrogin-1 and MAPK activation. UA-treated VSMCs showed an increased migratory rate as compared to control cells ( < 0.001) and a re-arrangement of F-actin. Probenecid, proteasome inhibition and ARBs prevented the development of dysfunctional VSMC. This study shows, for the first time, that UA-induced cytoskeleton changes determine an increase in VSMC migratory rate, suggesting UA as a key player in vascular remodeling.
高尿酸血症通过何种机制诱导血管功能障碍并导致心血管疾病仍存在争议。表型转化是血管平滑肌细胞（VSMCs）参与器官损伤的一种特性。本研究旨在探讨尿酸（UA）对 VSMC 细胞骨架变化、细胞迁移以及参与这些过程的信号的影响。将小鼠 VSMC 株 MOVAS 与 6、9 和 12 mg/dL 的 UA、血管紧张素受体阻滞剂（ARBs）、蛋白酶体和 MEK 抑制剂孵育。在微趋化室和鬼笔环肽染色中评估迁移特性。通过 Western blot、免疫染色和定量逆转录 PCR 确定细胞骨架蛋白（Smoothelin B（SMTB）、α-平滑肌肌动蛋白（αSMA）、平滑肌 22α（SM22α））、Atrogin-1 和 MAPK 激活的变化。UA 暴露改变了 SMT、αSMA 和 SM22α 水平（<0.05），并显著上调了 Atrogin-1 和 MAPK 激活。与对照细胞相比，UA 处理的 VSMCs 的迁移率增加（<0.001），并伴有 F-肌动蛋白的重排。丙磺舒、蛋白酶体抑制和 ARBs 可预防功能性 VSMC 的发展。本研究首次表明，UA 诱导的细胞骨架变化决定了 VSMC 迁移率的增加，提示 UA 是血管重塑的关键因素。
