Ma Yeshuo, Zhang Zhen, Chen Runtai, Shi Rui, Zeng Pingyu, Chen Ruifang, Leng Yiping, Chen Alex F
Department of Cardiology, The Third Xiangya Hospital of Central South University , Changsha , China.
Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital of Central South University , Changsha , China.
Am J Physiol Heart Circ Physiol. 2019 May 1;316(5):H1039-H1046. doi: 10.1152/ajpheart.00746.2018. Epub 2019 Feb 15.
Endothelial inflammation plays an important role in hyperhomocysteinemia (HHcy)-associated vascular diseases. High mobility group box 1 (HMGB1) is a pro-inflammatory danger molecule produced by endothelial cells. However, whether HMGB1 is involved in vascular endothelial inflammation of HHcy is poorly understood. Neuropilin-1 (NRP1) mediates inflammatory response and activates mitogen-activated protein kinases (MAPKs) pathway that has been reported to be involved in regulation of HMGB1. The aim of this study was to determine the alteration of HMGB1 in HHcy, and the role of NRP1 in regulation of endothelial HMGB1 under high homocysteine (Hcy) condition. In the present study, we first observed that the plasma level of HMGB1 was elevated in HHcy patients and an experimental rat model, and increased HMGB1 was also observed in the thoracic aorta of an HHcy rat model. HMGB1 was induced by Hcy accompanied with upregulated NRP1 in vascular endothelial cells. Overexpression of NRP1 promoted expression and secretion of HMGB1 and endothelial inflammation; knockdown of NRP1 inhibited HMGB1 and endothelial inflammation induced by Hcy, which partially regulated through p38 MAPK pathway. Furthermore, NRP1 inhibitor ATWLPPR reduced plasma HMGB1 level and expression of HMGB1 in the thoracic aorta of HHcy rats. In conclusion, our data suggested that Hcy requires NRP1 to regulate expression and secretion of HMGB1. The present study provides the evidence for inhibition of NRP1 and HMGB1 to be the novel therapeutic targets of vascular endothelial inflammation in HHcy in the future. This study shows for the first time to our knowledge that the plasma level of high mobility group box 1 (HMGB1) is elevated in hyperhomocysteinemia (HHcy) patients, and homocysteine promotes expression and secretion of HMGB1 partially regulated by neuropilin-1 in endothelial cells, which is involved in endothelial inflammation. Most importantly, these new findings will provide a potential therapeutic strategy for vascular endothelial inflammation in HHcy.
内皮炎症在高同型半胱氨酸血症（HHcy）相关的血管疾病中起重要作用。高迁移率族蛋白B1（HMGB1）是一种由内皮细胞产生的促炎危险分子。然而，HMGB1是否参与HHcy的血管内皮炎症尚不清楚。神经纤毛蛋白-1（NRP1）介导炎症反应并激活丝裂原活化蛋白激酶（MAPKs）通路，据报道该通路参与HMGB1的调节。本研究的目的是确定HHcy中HMGB1的变化，以及NRP1在高同型半胱氨酸（Hcy）条件下对内皮HMGB1的调节作用。在本研究中，我们首先观察到HHcy患者和实验大鼠模型中血浆HMGB1水平升高，在HHcy大鼠模型的胸主动脉中也观察到HMGB1增加。Hcy诱导血管内皮细胞中HMGB1表达上调，同时NRP1也上调。NRP1的过表达促进了HMGB1的表达和分泌以及内皮炎症；敲低NRP1可抑制Hcy诱导的HMGB1和内皮炎症，这部分是通过p38 MAPK通路调节的。此外，NRP1抑制剂ATWLPPR降低了HHcy大鼠血浆HMGB1水平和胸主动脉中HMGB1的表达。总之，我们的数据表明Hcy需要NRP1来调节HMGB1的表达和分泌。本研究为抑制NRP1和HMGB1成为未来HHcy血管内皮炎症的新型治疗靶点提供了证据。据我们所知，本研究首次表明高迁移率族蛋白B1（HMGB1）在高同型半胱氨酸血症（HHcy）患者中血浆水平升高，同型半胱氨酸促进内皮细胞中HMGB1的表达和分泌，部分受神经纤毛蛋白-1调节，这与内皮炎症有关。最重要的是，这些新发现将为HHcy的血管内皮炎症提供一种潜在的治疗策略。
