Serum exosomes mediate delivery of arginase 1 as a novel mechanism for endothelial dysfunction in diabetes
Serum exosomes mediate delivery of arginase 1 as a novel mechanism for endothelial dysfunction in diabetes
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血清外泌体介导精氨酸酶 1 的递送作为糖尿病内皮功能障碍的新机制
DOI：
10.1073/pnas.1721521115
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发表时间：
2018-07-17
影响因子：
11.1
通讯作者：
Huang, Yu
中科院分区：
文献类型：
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作者：
Zhang, Huina;Liu, Jian;Huang, Yu
内皮功能障碍在糖尿病血管病变的发生发展中起着至关重要的作用，但其机制尚不完全清楚。在这项研究中，我们揭示了以前未定义的血清外泌体在调节糖尿病内皮功能和血管稳态中的重要性。通过比较蛋白质组学分析，发现糖尿病血清中的胞外体中富含胰蛋白酶1，并可转移至内皮细胞，抑制NO的产生，从而损害内皮功能。这是一种细胞与细胞之间的通讯机制，首次被确定为导致糖尿病血管功能障碍。外泌体，在血液中丰富，提供各种分子到受体细胞。内皮细胞直接暴露于循环物质。然而，内皮细胞如何对血清外泌体（SExos）做出反应以及其对糖尿病相关血管病变的影响从未被探索过。在本研究中，我们发现来自糖尿病db/db小鼠的SExos（db/db SExos）被主动脉内皮细胞摄取，这严重损害了非糖尿病db/m+小鼠的内皮功能。外泌体蛋白，而不是RNA，主要解释db/db SExos诱导的内皮功能障碍。比较蛋白质组学分析显示db/db SExos中的脱氢酶1显著增加。沉默或过度表达的dexase 1证实了其在db/db SExos诱导的内皮功能障碍中的重要作用。这项研究证明了SExos将β-淀粉酶1蛋白递送到内皮细胞，代表了糖尿病内皮功能障碍发展过程中的细胞机制。这一结果扩大了监测血管稳态的血液传播物质的范围。
Significance Endothelial dysfunction plays a crucial role in the development of diabetic vasculopathy, but the mechanisms are not fully understood. In this study, we have revealed a previously undefined importance of serum exosomes in regulating endothelial function and vascular homeostasis in diabetes. Through comparative proteomics analysis, arginase1 was found enriched in diabetic serum exosomes and can be transferred to endothelial cells to inhibit NO production, thus impairing endothelial function. This is a cell-to-cell communication mechanism first identified to contribute to vascular dysfunction in diabetes. Exosomes, abundant in blood, deliver various molecules to recipient cells. Endothelial cells are directly exposed to circulating substances. However, how endothelial cells respond to serum exosomes (SExos) and the implications in diabetes-associated vasculopathy have never been explored. In the present study, we showed that SExos from diabetic db/db mice (db/db SExos) were taken up by aortic endothelial cells, which severely impaired endothelial function in nondiabetic db/m+ mice. The exosomal proteins, rather than RNAs, mostly account for db/db SExos-induced endothelial dysfunction. Comparative proteomics analysis showed significant increase of arginase 1 in db/db SExos. Silence or overexpression of arginase 1 confirmed its essential role in db/db SExos-induced endothelial dysfunction. This study is a demonstration that SExos deliver arginase 1 protein to endothelial cells, representing a cellular mechanism during development of diabetic endothelial dysfunction. The results expand the scope of blood-borne substances that monitor vascular homeostasis.