NRP1 regulates HMGB1 in vascular endothelial cells under high homocysteine condition

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.

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Histidine-Rich Glycoprotein Inhibits High Mobility Group Box 1-Mediated Pathways in Vascular Endothelial Cells

SSRN Electronic Journal ◽

10.2139/ssrn.3502358 ◽

2019 ◽

Author(s):

Shangze Gao ◽

Hidenori Wake ◽

Masakiyo Sakaguchi ◽

Dengli Wang ◽

Youhei Takahashi ◽

...

Keyword(s):

Endothelial Cells ◽

Vascular Endothelial Cells ◽

High Mobility ◽

High Mobility Group ◽

Vascular Endothelial

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High-mobility group box 1 protein induces tissue factor expression in vascular endothelial cells via activation of NF-κB and Egr-1

Thrombosis and Haemostasis ◽

10.1160/th08-11-0759 ◽

2009 ◽

Vol 102 (08) ◽

pp. 352-359 ◽

Cited By ~ 29

Author(s):

Haichao Wang ◽

Yiting Tang ◽

Zhang Fan ◽

Ben Lv ◽

Xianzhong Xiao ◽

...

Keyword(s):

Endothelial Cells ◽

Cell Surface ◽

Tissue Factor ◽

Vascular Endothelial Cells ◽

High Mobility ◽

High Mobility Group ◽

Cell Surface Receptors ◽

Dependent Manner ◽

Vascular Endothelial ◽

Surface Receptors

SummaryHigh-mobility group box 1 protein (HMGB1), an abundant nuclear protein, was recently established as a proinflammatory mediator of experimental sepsis.Although extracellular HMGB1 has been found in atherosclerotic plaques, its potential role in the pathogenesis of atherothrombosis remains elusive. In the present study, we determined whether HMGB1 induces tissue factor (TF) expression in vascular endothelial cells (ECs) and macrophages. Our data showed that HMGB1 stimulated ECs to express TF (but not TF pathway inhibitor) mRNA and protein in a concentration and time-dependent manner. Blockade of cell surface receptors (including TLR4, TLR2, and RAGE) with specific neutralising antibodies partially reduced HMGB1-induced TF expression. Moreover, HMGB1 increased expression of Egr-1 and nuclear translocation of NF-κB (c-Rel/p65) in ECs. Taken together, our data suggest that HMGB1 induces TF expression in vascular endothelial cells via cell surface receptors (TLR4, TLR2, and RAGE), and through activation of transcription factors (NF-κB and Egr-1).

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Histidine-rich glycoprotein inhibits high mobility group box 1-mediated signal pathway in vascular endothelial cells

Proceedings for Annual Meeting of The Japanese Pharmacological Society ◽

10.1254/jpssuppl.92.0_1-yia-06 ◽

2019 ◽

Vol 92 (0) ◽

pp. 1-YIA-06

Author(s):

Shangze Gao ◽

Hidenori Wake ◽

Yuan Gao ◽

Dengli Wang ◽

Keyue Liu ◽

...

Keyword(s):

Endothelial Cells ◽

Vascular Endothelial Cells ◽

High Mobility ◽

Signal Pathway ◽

High Mobility Group ◽

Vascular Endothelial

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Histidine-Rich Glycoprotein Inhibits High-Mobility Group Box-1-Mediated Pathways in Vascular Endothelial Cells through CLEC-1A

iScience ◽

10.1016/j.isci.2020.101180 ◽

2020 ◽

Vol 23 (6) ◽

pp. 101180

Author(s):

Shangze Gao ◽

Hidenori Wake ◽

Masakiyo Sakaguchi ◽

Dengli Wang ◽

Youhei Takahashi ◽

...

Keyword(s):

Endothelial Cells ◽

Vascular Endothelial Cells ◽

High Mobility ◽

High Mobility Group ◽

Vascular Endothelial

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Abstract 9483: High Mobility Group Box 1 Promotes Angiogenesis From Bone Marrow-Derived Endothelial Progenitor Cells After Myocardial Infarction

Circulation ◽

10.1161/circ.130.suppl_2.9483 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Yuichi Nakamura ◽

Satoshi Suzuki ◽

Takeshi Shimizu ◽

Makiko Miyata ◽

Tetsuro Shishido ◽

...

Keyword(s):

Myocardial Infarction ◽

Bone Marrow ◽

Endothelial Cells ◽

Progenitor Cells ◽

Endothelial Progenitor Cells ◽

Vascular Endothelial Cells ◽

High Mobility ◽

High Mobility Group ◽

Vascular Endothelial ◽

Double Positive

Background: High mobility group box 1 (HMGB1) is a DNA-binding protein secreted into extracellular space from necrotic cells and acts as a cytokine. We have reported that HMGB1 attenuates cardiac damage and restores cardiac function by enhancing angiogenesis after myocardial infarction (MI). We examined the role of HMGB1 in angiogenesis from bone marrow (BM) -derived cells in the heart, using transgenic mice with cardiac-specific overexpression of HMGB1 (HMGB1-TG). Methods and Results: HMGB1-TG mice and wild-type littermate (WT) mice were lethally irradiated and injected with BM cells from green fluorescent protein (GFP) mice through the tail vein. Two weeks after BM transplantation, the left anterior descending artery was ligated to create MI. In flow cytometry analysis, GFP-positive cells were identified as donor BM cells-derived endothelial progenitor cells (EPC) if they were positive for both CD34 and CD144 in granulocyte differentiation antigen-1-negative fraction. Circulating EPC mobilized from BM was increased at 1 week after MI in HMGB1-TG mice compared with WT mice (41.9% vs. 24.5%, P < 0.01). Histological examination showed the size of MI was smaller in HMGB1-TG mice than in WT mice (42.9% vs. 59.1%, P < 0.01) at 4 weeks after MI. In myocardial immunofluorescence staining, GFP and CD31 double-positive cells were BM-derived cells engrafted within myocardial tissue as vascular endothelial cells of new capillaries or arterioles. The ratio of these double positive cells to all cardiac cells was significantly higher in the HMGB1-TG mice than in the WT mice (8.3% vs. 2.9%, P < 0.01). Enzyme-linked immunosorbent assay revealed that the levels of cardiac vascular endothelial growth factor at 1 week after MI were higher in HMGB1-TG mice than in WT mice (642.1 vs. 390.7 pg/dl, P < 0.05). Conclusions: The present study demonstrated the direct in vivo evidence that HMGB1 promoted angiogenesis and reduced MI size by enhancing mobilization and differentiation of BM cells to EPC, migration to the border zone of MI, and engraftment as vascular endothelial cells of new capillaries or arterioles in the infarcted heart.

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Inhibition of the JAK2/STAT3/SOSC1 Signaling Pathway Improves Secretion Function of Vascular Endothelial Cells in a Rat Model of Pregnancy-Induced Hypertension

Cellular Physiology and Biochemistry ◽

10.1159/000452566 ◽

2016 ◽

Vol 40 (3-4) ◽

pp. 527-537 ◽

Cited By ~ 4

Author(s):

Jian-Ying Luo ◽

Dan Fu ◽

Ya-Qin Wu ◽

Ying Gao

Keyword(s):

Endothelial Cells ◽

Signaling Pathway ◽

Rat Model ◽

Vascular Endothelial Cells ◽

Serum Levels ◽

Vascular Endothelial ◽

Pregnancy Induced Hypertension ◽

Pregnant Rats ◽

Tnf Α ◽

Induced Hypertension

Background/Aims: The present study aimed to investigate the effects of the JAK2/STAT3/SOSC1 signaling pathway on the secretion function of vascular endothelial cells (VECs) in a rat model of pregnancy-induced hypertension (PIH). Methods: A PIH rat model was established. Forty-eight pregnant Sprague-Dawley female rats were selected and assigned into four groups: the normal group (normal non-pregnant rats), the non-PIH group (pregnant rats without PIH), the PIH group (pregnant rats with PIH) and the AG490 group (pregnant rats with PIH treated with AG490). Systolic blood pressure (SBP) and urinary protein (UP) were measured. The expressions of JAK2/STAT3/SOSC1 signaling pathway-related proteins in placenta tissues were detect by Western blotting. Radioimmunoassay was applied to detect serum levels of nitric oxide (NO), super oxide dismutase (SOD), placental growth factor (PGF), thromboxane B2 (TXB2) and endothelin (ET). Enzyme-linked immunosorbent assay (ELISA) was used to determine serum levels of interleukin-6 (IL-6), interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α). Results: Compared with the normal and non-PIH groups, the PIH and AG490 groups had higher SBP and UP levels at 17th and 25th day of pregnancy. The expressions of p/t-JAK2, p/t-STAT3 and SOSC1 in the PIH and AG490 groups were higher than those in the non-PIH group, while the expressions of p/t-JAK2, p/t-STAT3 and SOSC1 in the AG490 group were lower than those in the PIH group. Compared with the non-PIH group, serum levels of ET, TXB2, IL-6 and TNF-α were increased in the PIH and AG490 groups, while serum levels of NO, SOD, 6-keto-PGF1a and IL-10 levels were reduced. Furthermore, the AG490 had lower serum levels of ET, TXB2, IL-6 and TNF-α and higher serum levels of NO, SOD, 6-keto-PGF1a and IL-10 than those in the PIH group. Conclusion: Our study provides evidence that inhibition of the JAK2/STAT3/SOSC1 signaling pathway could improve the secretion function of VECs in PIH rats.

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miR-320 regulates tumor angiogenesis driven by vascular endothelial cells in oral cancer by silencing neuropilin 1

Angiogenesis ◽

10.1007/s10456-013-9394-1 ◽

2013 ◽

Vol 17 (1) ◽

pp. 247-260 ◽

Cited By ~ 77

Author(s):

Yi-Ying Wu ◽

Yuh-Ling Chen ◽

Yun-Chia Jao ◽

I-Shan Hsieh ◽

Kung-Chao Chang ◽

...

Keyword(s):

Endothelial Cells ◽

Oral Cancer ◽

Tumor Angiogenesis ◽

Vascular Endothelial Cells ◽

Vascular Endothelial ◽

Neuropilin 1

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Protective effects of diosgenin in the hyperlipidemic rat model and in human vascular endothelial cells against hydrogen peroxide-induced apoptosis

Chemico-Biological Interactions ◽

10.1016/j.cbi.2010.02.005 ◽

2010 ◽

Vol 184 (3) ◽

pp. 366-375 ◽

Cited By ~ 55

Author(s):

Guohua Gong ◽

Yuan Qin ◽

Wen Huang ◽

Shu Zhou ◽

Xiaohua Wu ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Endothelial Cells ◽

Rat Model ◽

Vascular Endothelial Cells ◽

Vascular Endothelial ◽

Protective Effects ◽

Induced Apoptosis

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Factors influencing the expression of stress fibers in vascular endothelial cells in situ.

The Journal of Cell Biology ◽

10.1083/jcb.97.2.416 ◽

1983 ◽

Vol 97 (2) ◽

pp. 416-424 ◽

Cited By ~ 151

Author(s):

G E White ◽

M A Gimbrone ◽

K Fujiwara

Keyword(s):

Endothelial Cells ◽

Thoracic Aorta ◽

Spontaneously Hypertensive Rats ◽

Vascular Endothelial Cells ◽

Stress Fibers ◽

Vascular Endothelial ◽

Descending Thoracic Aorta ◽

Hypertensive Rats ◽

Spontaneously Hypertensive

The organization of actin and myosin in vascular endothelial cells in situ was studied by immunofluorescence microscopy. Examination of perfusion-fixed, whole mounts of normal mouse and rat descending thoracic aorta revealed the presence of axially oriented stress fibers containing both actin and myosin within the endothelial cells. In both species, the proportion of cells containing stress fibers varied from region to region within the same vessel. Some endothelial cells in mouse mesenteric vein and in rat inferior vena cava also contained stress fibers. Quantitative studies of the proportion of endothelial cells containing stress fibers in the descending thoracic aorta of age-matched normotensive and spontaneously hypertensive rats revealed significant differences. When animals of the same sex of the two strains were compared, the proportion was approximately two times greater in the spontaneously hypertensive rats. The proportion of endothelial cells containing stress fibers was about two times greater in males than in females of both strains. These observations suggest that multiple factors, including anatomical, sex, and hemodynamic differences, influence the organization of the endothelial cell cytoskeleton in situ.

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