Antibody-Mediated Endothelial Cell Damage Via Nitric Oxide

Lin, Yee‐Shin; Lin, Chun‐Min; Lei, Huan Yao; Liu, H. S.; Yeh, Trai Ming; Chen, S. H.; Liu, Cheng Chien

doi:10.2174/1381612043453469

Cited by 37 publications

(30 citation statements)

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“…We previously showed that anti-DV NS1 antibodies induced endothelial cell apoptosis by a NO-regulated pathway. 38,39 Other studies have reported the involvement of NO in hepatotoxicity, 34,[53][54][55] and that NO causes hepatocyte injury primarily by inducing apoptosis. 55,56 We found that dengue patient IgG-induced serum AST increase in mice was partially inhibited by NO synthase inhibitor L-NAME.…”

Section: Discussionmentioning

confidence: 99%

“…We previously demonstrated the involvement of nitric oxide (NO) in anti-DV NS1-induced endothelial cell apoptosis. 38,39 Using NO synthase inhibitor N o -nitro-L-arginine methyl ester (L-NAME) to investigate its protective effect in liver injury, we found that dengue patient IgG-induced mouse serum AST increase was partially inhibited by L-NAME (Figure 6b).…”

Section: Liver Injury In Dengue Patient Sera Igg-treated Micementioning

confidence: 99%

“…37 Cell apoptosis and inflammatory activation are the two major responses causing anti-DV NS1-induced endothelial cell damage. [38][39][40][41] To elucidate the effect of anti-DV NS1 in vivo, we used a murine model of active immunization with recombinant DV NS1 protein or passive immunization with antibodies obtained from mice immunized with DV NS1. We found liver damage in both active and passive immunization models, which supports a pathologic mechanism of liver injury mediated by anti-DV NS1 antibodies.…”

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confidence: 99%

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Liver injury caused by antibodies against dengue virus nonstructural protein 1 in a murine model

Lin

Wan

Chen

et al. 2008

Laboratory Investigation

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Clinical manifestations of severe dengue diseases include thrombocytopenia, vascular leakage, and liver damage. Evidence shows that hepatic injury is involved in the pathogenesis of dengue infection; however, the mechanisms are not fully resolved. Our previous in vitro studies suggested a mechanism of molecular mimicry in which antibodies directed against dengue virus (DV) nonstructural protein 1 (NS1) cross-reacted with endothelial cells and caused inflammatory activation and apoptosis. In this study, the pathogenic effects of anti-DV NS1 antibodies were further examined in a murine model. We found, in liver sections, that anti-DV NS1 antibodies bound to naive mouse vessel endothelium and the binding activity was inhibited by preabsorption of antibodies with DV NS1. Active immunization with DV NS1 resulted in antibody deposition to liver vessel endothelium, and also apoptotic cell death of liver endothelium. Liver tissue damage was observed in DV NS1-immunized mice by histological examination. The serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were increased in mice either actively immunized with DV NS1 protein or passively immunized with antibodies obtained from DV NS1-immunized mice. Furthermore, histological examination revealed mononuclear phagocyte infiltration and cell apoptosis in mice passively immunized with antibodies obtained from mice immunized with DV NS1. Increased AST and ALT levels were observed in mice passively immunized with purified immunoglobulin G (IgG) from dengue patients compared with normal control human IgG-immunized mice. The increased AST and ALT levels were inhibited when dengue patient serum IgG was preabsorbed with DV NS1. In conclusion, active immunization with DV NS1 protein causes immune-mediated liver injury in mice. Passive immunization provides additional evidence that anti-DV NS1 antibodies may play a role in liver damage, which is a pathologic manifestation in dengue virus disease.

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Section: Discussionmentioning

confidence: 99%

Section: Liver Injury In Dengue Patient Sera Igg-treated Micementioning

confidence: 99%

mentioning

confidence: 99%

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Liver injury caused by antibodies against dengue virus nonstructural protein 1 in a murine model

Lin

Wan

Chen

et al. 2008

Laboratory Investigation

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“…In particular, anti-endothelial cell Abs (AECAs) have been shown, at least partially, to be involved in vasculitis and endothelial cell dysfunction in patients with lupus, systemic sclerosis, thrombocytopenic purpura, and with microbial infections, such as dengue virus (DENV), hepatitis C virus, CMV, and group A Streptococcus (2-4). The vascular dysfunction induced by AECAs can be mediated through direct targeting to cell-surface autoantigens followed by stimulating or blocking their intracellular signaling, or indirectly linking to immune cells, such as neutrophils, monocytes, and NK cells to cause complement-and Ab-dependent cytotoxicity, as well as vessel inflammation (4)(5)(6). The mechanisms of autoantibody generation after autoantigen exposure are important issues to explore.…”

mentioning

confidence: 99%

“…Anti-DENV NS1 Abs cause inducible NO synthase (iNOS) expression and NO production in endothelial cells, which lead to NO-mediated cell apoptosis (4,26). Anti-DENV NS1 Abs also induce NF-kB-regulated inflammatory activation, including cytokine production and adhesion molecule expression (27).…”

mentioning

confidence: 99%

Anti–Dengue Virus Nonstructural Protein 1 Antibodies Cause NO-Mediated Endothelial Cell Apoptosis via Ceramide-Regulated Glycogen Synthase Kinase-3β and NF-κB Activation

Chen

Lin

Wan

et al. 2013

The Journal of Immunology

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Immunopathogenetic mechanisms of dengue virus (DENV) infection are involved in hemorrhagic syndrome resulting from thrombocytopenia, coagulopathy, and vasculopathy. We have proposed a mechanism of molecular mimicry in which Abs against DENV nonstructural protein 1 (NS1) cross-react with human endothelial cells and cause NF-κB–regulated immune activation and NO-mediated apoptosis. However, the signaling pathway leading to NF-κB activation after the binding of anti-DENV NS1 Abs to endothelial cells is unresolved. In this study, we found that anti-DENV NS1 Abs caused the formation of lipid raftlike structures, and that disrupting lipid raft formation by methyl-β-cyclodextrin decreased NO production and apoptosis. Treatment with anti-DENV NS1 Abs elevated ceramide generation in lipid rafts. Pharmacological inhibition of acid sphingomyelinase (aSMase) decreased anti-DENV NS1 Ab-mediated ceramide and NO production, as well as apoptosis. Exogenous ceramide treatment induced biogenesis of inducible NO synthase (iNOS)/NO and apoptosis through an NF-κB–regulated manner. Furthermore, activation of glycogen synthase kinase-3β (GSK-3β) was required for ceramide-induced NF-κB activation and iNOS expression. Notably, anti-DENV NS1 Abs caused GSK-3β–mediated NF-κB activation and iNOS expression, which were regulated by aSMase. Moreover, pharmacological inhibition of GSK-3β reduced hepatic endothelial cell apoptosis in mice passively administered anti-DENV NS1 Abs. These results suggest that anti-DENV NS1 Abs bind to the endothelial cell membrane and cause NO production and apoptosis via a mechanism involving the aSMase/ceramide/GSK-3β/NF-κB/iNOS/NO signaling pathway.

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Assessment of Biocompatibility of 3D‐Printed Cardiovascular Stent

Veerubhotla

McGraw

Lee

2023

Advanced Therapeutics

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This study aims to evaluate the biocompatibility of the 3D‐printed stent and its efficiency on reducing the oxidized‐low‐density lipoprotein (ox‐LDL) damage in endothelial cells using the zebrafish embryos model. The human umbilical vein endothelial cells (HUVECs) significantly (p‐value <0.001) lose their viability upon exposure to ox‐LDL treatment (100 µg/ml). An exposure of HUVECs to resveratrol (RSL)‐unloaded 3D stent slightly lowers the cell viability as compared with untreated control group. On the contrary, RSL‐loaded 3D stent exposure groups maintain initial cell viability. The amounts of TNF‐α and IL‐β released from zebrafish embryos (1.82 ± 0.75 and 1.87 ± 0.24) in the group treated with the RSL‐loaded 3D stents are significantly lower (p < 0.001) than those from the LPS alone treated group (8.13 ± 2.29 and 23.79 ± 3.82, respectively). It is found that RSL‐loaded 3D stent at a RSL dose of 1 mm shows no mortality during the developmental stages, but RSL‐loaded 3D stent at a dose of 2 mm shows a lowered survival rate (93.3 ± 3.3%), shorter length of larvae, pericardial and yolk sac edemas of 53.3 ± 23.3% and 3.3 ± 3.3%, respectively. The RSL‐loaded 3D stents efficiently downregulate the proinflammatory cytokines, and protect an organism against oxidative stress, while producing minimal developments defects in zebrafish embryos.

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Antibody-Mediated Endothelial Cell Damage Via Nitric Oxide

Cited by 37 publications

References 0 publications

Liver injury caused by antibodies against dengue virus nonstructural protein 1 in a murine model

Liver injury caused by antibodies against dengue virus nonstructural protein 1 in a murine model

Anti–Dengue Virus Nonstructural Protein 1 Antibodies Cause NO-Mediated Endothelial Cell Apoptosis via Ceramide-Regulated Glycogen Synthase Kinase-3β and NF-κB Activation

Assessment of Biocompatibility of 3D‐Printed Cardiovascular Stent

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