Collado Aida, Humoud Rawan, Kontidou Eftychia, Eldh Maria, Swaich Jasmin, Zhao Allan, Yang Jiangning, Jiao Tong, Domingo Elena, Carlestål Emelie, Mahdi Ali, Tengbom John, Végvári Ákos, Deng Qiaolin, Alvarsson Michael, Gabrielsson Susanne, Eriksson Per, Zhou Zhichao, Pernow John
Division of Cardiology and.
Division of Immunology and Respiratory Medicine, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
J Clin Invest. 2025 Mar 20;135(10). doi: 10.1172/JCI180900. eCollection 2025 May 15.
Red blood cells (RBCs) induce endothelial dysfunction in type 2 diabetes (T2D), but the mechanism by which RBCs communicate with the endothelium is unknown. This study tested the hypothesis that extracellular vesicles (EVs) secreted by RBCs act as mediators of endothelial dysfunction in T2D. Despite a lower production of EVs derived from RBCs of T2D patients (T2D RBC-EVs), their uptake by endothelial cells was greater than that of EVs derived from RBCs of healthy individuals (H RBC-EVs). T2D RBC-EVs impaired endothelium-dependent relaxation, and this effect was attenuated following inhibition of arginase in EVs. Inhibition of vascular arginase or oxidative stress also attenuated endothelial dysfunction induced by T2D RBC-EVs. Arginase-1 was detected in RBC-derived EVs, and arginase-1 and oxidative stress were increased in endothelial cells following coincubation with T2D RBC-EVs. T2D RBC-EVs also increased arginase-1 protein in endothelial cells following mRNA silencing and in the endothelium of aortas from endothelial cell arginase-1-knockout mice. It is concluded that T2D-RBCs induce endothelial dysfunction through increased uptake of EVs that transfer arginase-1 from RBCs to the endothelium to induce oxidative stress and endothelial dysfunction. These results shed important light on the mechanism underlying endothelial dysfunction mediated by RBCs in T2D.
红细胞（RBCs）可导致2型糖尿病（T2D）患者的内皮功能障碍，但其与内皮细胞之间的通讯机制尚不清楚。本研究验证了一个假设，即红细胞分泌的细胞外囊泡（EVs）是T2D患者内皮功能障碍的介导因子。尽管T2D患者红细胞来源的细胞外囊泡（T2D RBC-EVs）产量较低，但其被内皮细胞摄取的量却高于健康个体红细胞来源的细胞外囊泡（H RBC-EVs）。T2D RBC-EVs损害内皮依赖性舒张功能，而在抑制细胞外囊泡中的精氨酸酶后，这种作用减弱。抑制血管精氨酸酶或氧化应激也可减轻T2D RBC-EVs诱导的内皮功能障碍。在红细胞来源的细胞外囊泡中检测到精氨酸酶-1，与T2D RBC-EVs共同孵育后，内皮细胞中的精氨酸酶-1和氧化应激增加。在mRNA沉默后，T2D RBC-EVs还可增加内皮细胞中的精氨酸酶-1蛋白水平，在来自内皮细胞精氨酸酶-1基因敲除小鼠的主动脉内皮中也是如此。研究得出结论，T2D红细胞通过增加对细胞外囊泡的摄取来诱导内皮功能障碍，这些细胞外囊泡将精氨酸酶-1从红细胞转移至内皮细胞，从而诱导氧化应激和内皮功能障碍。这些结果为T2D中红细胞介导的内皮功能障碍的潜在机制提供了重要线索。
