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Am J Physiol Heart Circ Physiol. 2019 May 1;316(5):H1039-H1046. doi: 10.1152/ajpheart.00746.2018. Epub 2019 Feb 15.

NRP1 regulates HMGB1 in vascular endothelial cells under high homocysteine condition.

Ma Y1,2, Zhang Z2,3, Chen R1,2, Shi R2,4, Zeng P2,3, Chen R1,2, Leng Y2, Chen AF1,2.

Author information

1
Department of Cardiology, The Third Xiangya Hospital of Central South University , Changsha , China.
2
Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital of Central South University , Changsha , China.
3
Centre for Experimental Medicine, The Third Xiangya Hospital of Central South University , Changsha , China.
4
Xiangya School of Pharmaceutical Sciences, Central South University , Changsha , China.

Abstract

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. NEW & NOTEWORTHY 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.

KEYWORDS:

HMGB1; endothelial inflammation; homocysteine; hyperhomocysteinemia; neuropilin-1

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