PMID- 30767669 OWN - NLM STAT- MEDLINE DCOM- 20200316 LR - 20210510 IS - 1522-1539 (Electronic) IS - 0363-6135 (Linking) VI - 316 IP - 5 DP - 2019 May 1 TI - NRP1 regulates HMGB1 in vascular endothelial cells under high homocysteine condition. PG - H1039-H1046 LID - 10.1152/ajpheart.00746.2018 [doi] AB - 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. FAU - Ma, Yeshuo AU - Ma Y AD - Department of Cardiology, The Third Xiangya Hospital of Central South University , Changsha , China. AD - Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital of Central South University , Changsha , China. FAU - Zhang, Zhen AU - Zhang Z AD - Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital of Central South University , Changsha , China. AD - Centre for Experimental Medicine, The Third Xiangya Hospital of Central South University , Changsha , China. FAU - Chen, Runtai AU - Chen R AD - Department of Cardiology, The Third Xiangya Hospital of Central South University , Changsha , China. AD - Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital of Central South University , Changsha , China. FAU - Shi, Rui AU - Shi R AD - Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital of Central South University , Changsha , China. AD - Xiangya School of Pharmaceutical Sciences, Central South University , Changsha , China. FAU - Zeng, Pingyu AU - Zeng P AD - Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital of Central South University , Changsha , China. AD - Centre for Experimental Medicine, The Third Xiangya Hospital of Central South University , Changsha , China. FAU - Chen, Ruifang AU - Chen R AD - Department of Cardiology, The Third Xiangya Hospital of Central South University , Changsha , China. AD - Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital of Central South University , Changsha , China. FAU - Leng, Yiping AU - Leng Y AD - Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital of Central South University , Changsha , China. FAU - Chen, Alex F AU - Chen AF AD - Department of Cardiology, The Third Xiangya Hospital of Central South University , Changsha , China. AD - Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital of Central South University , Changsha , China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190215 PL - United States TA - Am J Physiol Heart Circ Physiol JT - American journal of physiology. Heart and circulatory physiology JID - 100901228 RN - 0 (Biomarkers) RN - 0 (HMGB1 Protein) RN - 0 (HMGB1 protein, human) RN - 0 (Hbp1 protein, rat) RN - 0 (Inflammation Mediators) RN - 0 (NRP1 protein, human) RN - 0LVT1QZ0BA (Homocysteine) RN - 144713-63-3 (Neuropilin-1) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) SB - IM MH - Adult MH - Animals MH - Biomarkers/blood MH - Case-Control Studies MH - Coculture Techniques MH - Disease Models, Animal MH - Female MH - HMGB1 Protein/*metabolism MH - Homocysteine/*blood MH - Human Umbilical Vein Endothelial Cells/*metabolism MH - Humans MH - Hyperhomocysteinemia/blood/genetics/*metabolism MH - Inflammation/blood/genetics/*metabolism MH - Inflammation Mediators/*metabolism MH - Male MH - Middle Aged MH - Neuropilin-1/genetics/*metabolism MH - Rats, Sprague-Dawley MH - Signal Transduction MH - THP-1 Cells MH - Up-Regulation MH - p38 Mitogen-Activated Protein Kinases/metabolism OTO - NOTNLM OT - HMGB1 OT - endothelial inflammation OT - homocysteine OT - hyperhomocysteinemia OT - neuropilin-1 EDAT- 2019/02/16 06:00 MHDA- 2020/03/17 06:00 CRDT- 2019/02/16 06:00 PHST- 2019/02/16 06:00 [pubmed] PHST- 2020/03/17 06:00 [medline] PHST- 2019/02/16 06:00 [entrez] AID - 10.1152/ajpheart.00746.2018 [doi] PST - ppublish SO - Am J Physiol Heart Circ Physiol. 2019 May 1;316(5):H1039-H1046. doi: 10.1152/ajpheart.00746.2018. Epub 2019 Feb 15.