Department of Vascular & Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Road II, Shanghai, 200025, China.
Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
BMC Biol. 2023 Jul 10;21(1):151. doi: 10.1186/s12915-023-01641-y.
Chronic kidney disease (CKD) accelerates atherosclerosis, but the mechanisms remain unclear. Tyrosine sulfation has been recognized as a key post-translational modification (PTM) in regulation of various cellular processes, and the sulfated adhesion molecules and chemokine receptors have been shown to participate in the pathogenesis of atherosclerosis via enhancement of monocyte/macrophage function. The levels of inorganic sulfate, the essential substrate for the sulfation reaction, are dramatically increased in patients with CKD, which indicates a change of sulfation status in CKD patients. Thus, in the present study, we detected the sulfation status in CKD patients and probed into the impact of sulfation on CKD-related atherosclerosis by targeting tyrosine sulfation function.
PBMCs from individuals with CKD showed higher amounts of total sulfotyrosine and tyrosylprotein sulfotransferase (TPST) type 1 and 2 protein levels. The plasma level of O-sulfotyrosine, the metabolic end product of tyrosine sulfation, increased significantly in CKD patients. Statistically, O-sulfotyrosine and the coronary atherosclerosis severity SYNTAX score positively correlated. Mechanically, more sulfate-positive nucleated cells in peripheral blood and more abundant infiltration of sulfated macrophages in deteriorated vascular plaques in CKD ApoE null mice were noted. Knockout of TPST1 and TPST2 decreased atherosclerosis and peritoneal macrophage adherence and migration in CKD condition. The sulfation of the chemokine receptors, CCR2 and CCR5, was increased in PBMCs from CKD patients.
CKD is associated with increased sulfation status. Increased sulfation contributes to monocyte/macrophage activation and might be involved in CKD-related atherosclerosis. Inhibition of sulfation may suppress CKD-related atherosclerosis and is worthy of further study.
慢性肾脏病（CKD）会加速动脉粥样硬化，但具体机制尚不清楚。酪氨酸硫酸化已被认为是调节各种细胞过程的关键翻译后修饰（PTM），硫酸化黏附分子和趋化因子受体已被证明通过增强单核细胞/巨噬细胞功能参与动脉粥样硬化的发病机制。CKD 患者无机硫酸盐（硫酸化反应的必需底物）水平显著升高，这表明 CKD 患者的硫酸化状态发生了变化。因此，本研究通过靶向酪氨酸硫酸化功能，检测 CKD 患者的硫酸化状态，并探讨硫酸化对 CKD 相关动脉粥样硬化的影响。
CKD 个体的 PBMC 显示出更高的总硫酸酪氨酸和酪氨酸蛋白硫酸转移酶（TPST）1 和 2 蛋白水平。CKD 患者的血浆 O-硫酸酪氨酸水平（酪氨酸硫酸化的代谢终产物）显著升高。统计学上，O-硫酸酪氨酸与冠状动脉粥样硬化严重程度 SYNTAX 评分呈正相关。在机制上，在 CKD ApoE 基因敲除小鼠中，外周血中带硫酸基团的有核细胞增多，血管斑块中硫酸化巨噬细胞浸润增多。TPST1 和 TPST2 基因敲除可减少 CKD 条件下的动脉粥样硬化和腹膜巨噬细胞黏附和迁移。CKD 患者 PBMC 中的趋化因子受体 CCR2 和 CCR5 的硫酸化增加。
CKD 与硫酸化状态增加有关。硫酸化增加导致单核细胞/巨噬细胞活化，可能与 CKD 相关的动脉粥样硬化有关。抑制硫酸化可能抑制 CKD 相关的动脉粥样硬化，值得进一步研究。
