Identification of VLDLR as a novel endothelial cell receptor for fibrin that modulates fibrin-dependent transendothelial migration of leukocytes

Yakovlev, Sergiy; Mikhailenko, Irina; Cao, Chunzhang; Zhang, Li; Strickland, Dudley K.; Medved, Leonid

doi:10.1182/blood-2011-09-382580

Cited by 42 publications

(132 citation statements)

References 31 publications

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“…With regard to endothelial cells, there were some interesting findings. VLDLr, as a novel endothelial cell receptor for fibrin, promoted fibrin-dependent leukocyte transmigration and thereby inflammation [7]. The suppression of endothelial cell proliferation by tissue factor pathway inhibitor was mediated by VLDLr [25].…”

Section: Discussionmentioning

confidence: 99%

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SalA Attenuates Hypoxia-Induced Endothelial Endoplasmic Reticulum Stress and Apoptosis via Down-Regulation of VLDL Receptor Expression

Xie¹,

Duan

Guo³

et al. 2015

Cell Physiol Biochem

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Background: Salvianolic acid A (SalA) has been shown to display robust protection against endothelial injury. VLDL receptor (VLDLr) is expressed at high levels in the endothelial cells. However its endothelial biological function has not been completely elucidated. Here, we investigated molecular effects of SalA on endothelial VLDLr expression, ER stress, and apoptosis under hypoxia condition. Methods: Human umbilical vein endothelial cells (HUVECs) pretreated with SalA were subjected to hypoxia stimulation. Endothelial ER stress and apoptosis were examined. The mRNA levels were tested by real-time RT-PCR, and the protein levels were determined by immunoblot analysis. Results: Pretreatment of HUVECs with SalA markedly attenuated hypoxia-induced endothelial ER stress and apoptosis. Hypoxia resulted in enhancement of VLDLr expression, which was effectively inhibited by SalA pretreatment. Furthermore, luciferase reporter gene assays indicated that SalA inhibited vldlr gene promoter activity, and ChIP assays showed that hypoxia increase the recruitment of HIF-1α to the vldlr gene promoter, and this process was hampered markedly by pretreatment of SalA. Finally, overexpression of VLDLr abolished SalA-mediated protection of endothelial cells from ER stress and apoptosis. Knockdown of VLDLr mimicked SalA protective effect. Conclusion: These results for the first time demonstrate that SalA protects against hypoxia-induced endothelial ER stress and apoptosis through inhibiting recruitment of HIF-1α to vldlr gene promoter and thus suppressing VLDLr expression.

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Section: Discussionmentioning

confidence: 99%

“…VLDLr was involved in the activation of retinal vascular endothelial cells and promotion of angiogenesis [5,6]. Further, fibrin-dependent transendothelial migration of leukocytes was found to be associated with VLDLr [7]. VLDL receptor was mediated in microvascular endothelial cells to inhibit cell division [8].…”

Section: Introductionmentioning

confidence: 99%

SalA Attenuates Hypoxia-Induced Endothelial Endoplasmic Reticulum Stress and Apoptosis via Down-Regulation of VLDL Receptor Expression

Xie¹,

Duan

Guo³

et al. 2015

Cell Physiol Biochem

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“…8,[30][31][32][33] This region has also been directly correlated with adhesion events. [34][35][36] Fibrinogen aC region (221-610) is composed of a flexible aC connector (221-391) and a more structured aC domain (392-610). 4,7 During fibrin polymerization, crosslinking in the aC region has been shown to promote lateral aggregation and protofibril staggering.…”

Section: Introductionmentioning

confidence: 99%

Ranking reactive glutamines in the fibrinogen αC region that are targeted by blood coagulant factor XIII

Mouapi

Bell

Smith

et al. 2016

Blood

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Key Points• FXIIIa exhibits a preference for Q237 in crosslinking reactions within fibrinogen aC (233-425) followed by Q328 and Q366.• None of the reactive glutamines in aC 233-425 (Q237, Q328, and Q366) are required to react first before the others can crosslink.Factor XIIIa (FXIIIa) introduces covalent g-glutamyl-«-lysyl crosslinks into the blood clot network. These crosslinks involve both the g and a chains of fibrin. The C-terminal portion of the fibrin a chain extends into the aC region (210-610). Crosslinks within this region help generate a stiffer clot, which is more resistant to fibrinolysis. Fibrinogen aC (233-425) contains a binding site for FXIIIa and three glutamines Q237, Q328, and Q366 that each participate in physiological crosslinking reactions. Although these glutamines were previously identified, their reactivities toward FXIIIa have not been ranked. Matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry and nuclear magnetic resonance (NMR) methods were thus used to directly characterize these three glutamines and probe for sources of FXIIIa substrate specificity. Glycine ethyl ester (GEE) and ammonium chloride served as replacements for lysine. Mass spectrometry and 2D heteronuclear single quantum coherence NMR revealed that Q237 is rapidly crosslinked first by FXIIIa followed by Q366 and Q328. Both N-GEE could be crosslinked to the three glutamines in aC (233-425) with a similar order of reactivity as observed with the MALDI-TOF mass spectrometry assay. NMR studies using the single aC mutants Q237N, Q328N, and Q366N demonstrated that no glutamine is dependent on another to react first in the series. Moreover, the remaining two glutamines of each mutant were both still reactive. Further characterization of Q237, Q328, and Q366 is important because they are located in a fibrinogen region susceptible to physiological truncations and mutation. The current results suggest that these glutamines play distinct roles in fibrin crosslinking and clot architecture. (Blood. 2016;127(18):2241-2248

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“…PAFAH catalyzes the degradation of platelet-activating factor and variants in the Plag2g7 gene have been associated with an increased risk of asthma and allergy (15). Endothelial cell VLDLR has also been identified as a fibrin receptor that promotes inflammation by facilitating the fibrin-dependent transmigration of leukocytes during vascular injury (16). This too may be relevant for asthma pathogenesis as fibrin deposition has been reported along the luminal surface of distal airways in an asthmatic patient and in a murine model of allergic airway inflammation (17).…”

Section: Introductionmentioning

confidence: 99%

The Very Low Density Lipoprotein Receptor Attenuates House Dust Mite–Induced Airway Inflammation by Suppressing Dendritic Cell–Mediated Adaptive Immune Responses

Fredriksson

Mishra

Lam

et al. 2014

The Journal of Immunology

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The very low density lipoprotein receptor (VLDLR) is a member of the low density lipoprotein receptor family that binds multiple ligands and plays a key role in brain development. Although the VLDLR mediates pleiotropic biological processes, only a limited amount of information is available regarding its role in adaptive immunity. Here, we identify an important role for the VLDLR in attenuating house dust mite (HDM)-induced airway inflammation in experimental murine asthma. We show that HDM-challenged Vldlr−/− mice have augmented eosinophilic and lymphocytic airway inflammation with increases in Th2 cytokines, C-C chemokines, IgE production and mucous cell metaplasia. A genome-wide analysis of the lung transcriptome identified that mRNA levels of CD209e (DC-SIGNR4), a murine homologue of DC-SIGN, were increased in the lungs of HDM-challenged Vldlr−/− mice, which suggested that the VLDLR might modify dendritic cell (DC) function. Consistent with this, VLDLR expression by human monocyte-derived DCs was increased by HDM stimulation. In addition, 55% of peripheral blood CD11c+ DCs from individuals with allergy expressed VLDLR under basal conditions. Lastly, the adoptive transfer of HDM-pulsed, CD11c+ bone marrow-derived DCs (BMDCs) from Vldlr−/− mice to the airways of wild type (WT) recipient mice induced augmented eosinophilic and lymphocytic airway inflammation upon HDM challenge with increases in Th2 cytokines, C-C chemokines, IgE production and mucous cell metaplasia, as compared to the adoptive transfer of HDM-pulsed, CD11c+ BMDCs from WT mice. Collectively, these results identify a novel role for the VLDLR as a negative regulator of DC-mediated adaptive immune responses in HDM-induced allergic airway inflammation.

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Identification of VLDLR as a novel endothelial cell receptor for fibrin that modulates fibrin-dependent transendothelial migration of leukocytes

Cited by 42 publications

References 31 publications

SalA Attenuates Hypoxia-Induced Endothelial Endoplasmic Reticulum Stress and Apoptosis via Down-Regulation of VLDL Receptor Expression

SalA Attenuates Hypoxia-Induced Endothelial Endoplasmic Reticulum Stress and Apoptosis via Down-Regulation of VLDL Receptor Expression

Ranking reactive glutamines in the fibrinogen αC region that are targeted by blood coagulant factor XIII

The Very Low Density Lipoprotein Receptor Attenuates House Dust Mite–Induced Airway Inflammation by Suppressing Dendritic Cell–Mediated Adaptive Immune Responses

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