Transgenic Expression of Human Thrombomodulin Inhibits HMGB1-Induced Porcine Aortic Endothelial Cell Activation

Bongoni, Anjan K.; Klymiuk, Nikolai; Wolf, Eckhard; Ayares, David; Rieben, Robert; Cowan, Peter J.

doi:10.1097/tp.0000000000001188

Cited by 18 publications

(21 citation statements)

References 20 publications

(23 reference statements)

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“…As vascular endothelial cells are critical in the antithrombotic system, Bongoni explored the role of thrombomodulin in HMGB-1-induced endothelial cell activation. He demonstrated that transgenic expression of thrombomodulin inhibited the activation of endothelial cells via increased HMGB-1-induced cleavage [143,176]. These findings indicated that HMGB-1 might serve as a potential target for anticoagulant drugs.…”

Section: Therapeutic Strategy For Hmgb-1mentioning

confidence: 88%

“…Recently, Kules and colleagues found that HMGB-1, an endothelial activation marker, was increased in dogs with babesiosis in parallel with elevated soluble urokinase receptor of plasminogen activator (suPAR), suggesting a possible role of HMGB-1 in fibrinolysis [142]. Besides, HMGB-1 has been shown to induce the formation of plasminogen activator inhibitor-1/tissue plasminogen activator (PAI-1/tPA) complexes, suggesting that HMGB-1 might prevent fibrinolysis via increased PAI-tPA complexes in endothelial cells [143]. Collectively, these data provided evidence that coagulation and fibrinolysis factors were involved in HMGB-1-induced thrombosis.…”

Section: Hmgb-1 and Coagulation And Fibrinolysis Factorsmentioning

confidence: 99%

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Emerging Role of High Mobility Group Box-1 in Thrombosis-Related Diseases

Pei

et al. 2018

Cell Physiol Biochem

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High mobility group box-1 (HMGB-1), a typical damage-associated molecular pattern protein released from various cells, was first identified in 1973. It is usually stored in the nuclei of cells. Several modifications of HMGB-1 promote its translocation to the cytosol, and it is actively or passively released from cells. When outside of the cells, HMGB-1is crucial in inflammation. It exerts its biological functions via interaction with its receptors, including receptor for advanced glycation end products (RAGE) and Toll-like receptor 4(TLR4). A large number of studies showed a close link between inflammation and thrombosis. This review demonstrated the increased expression of HMGB-1 in thrombosis-related diseases, including coronary artery disease, stroke, peripheral arterial disease, disseminated intravascular coagulation, and venous thrombosis. Besides, it summarized the current understanding of the emerging link between HMGB-1 and thrombosis from three aspects: platelet, NETs, and coagulation and fibrinolysis factors. Finally, it explored the possible therapeutic strategies targeting HMGB-1 for treating thrombosis-related diseases.

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Section: Therapeutic Strategy For Hmgb-1mentioning

confidence: 88%

Section: Hmgb-1 and Coagulation And Fibrinolysis Factorsmentioning

confidence: 99%

Emerging Role of High Mobility Group Box-1 in Thrombosis-Related Diseases

Pei

et al. 2018

Cell Physiol Biochem

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“…It exhibits its anti-inflammatory effect by regulating HMGB1. Recombinant soluble thrombomodulin ameliorated cerebral ischemic injury via an HMGB1 inhibitory mechanism in mice with middle cerebral artery occlusion and rats with cerebral vein sinus thrombosis [64,94]. In a rat model of sepsis, recombinant thrombomodulin suppressed thrombus formation and HMGB1 levels.…”

Section: Therapeutic Potential Of Hmgb1mentioning

confidence: 96%

“…Its effect on TF activity induced by HMGB1 is partly attenuated by 3 neutralizing antibodies (anti-TLR-2, anti-TLR-4, and anti-RAGE) and NF-κB/early growth response-1 (Egr-1) interference, suggesting that the TLR-2/TLR-4/RAGE and NF-κB/Egr-1 pathway mediates the HMGB1-induced expression of TF [93]. HMGB1 also induces the formation of the plasminogen activator inhibitor-1/tissue plasminogen activator (PAI-1/tPA) complexes, suggesting that it might prevent fibrinolysis via increased PAI-tPA complexes in endothelial cells [94]. Collectively, these data provide evidence that coagulation and fibrinolysis factors are involved in HMGB1-induced thrombosis.…”

Section: Hmgb1 Coagulation and Fibrinolysismentioning

confidence: 99%

Sterile Inflammatory Role of High Mobility Group Box 1 Protein: Biological Functions and Involvement in Disease

et al. 2018

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High mobility group box 1 protein (HMGB1), a sterile inflammatory molecule and damage-associated molecular pattern (DAMP) released from various cells during stress has been implicated in inflammation. Several reports show that there is a direct relationship between inflammation and cardiovascular diseases (CVDs) such as thrombosis, hypertension, insulin resistance, preeclampsia, etc. Here, we intend to summarize the concept of the emerging link between HMGB1 and CVDs. Furthermore, we will discuss the possible therapeutic strategies that target HMGB1 for the treatment of different CVDs.

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“…Plasma level of HMGB1 is elevated in the patients with diabetes mellitus [15], chronic inflammatory diseases such as systemic lupus erythematosus and rheumatoid arthritis [16,17] or sepsis [18]. In vitro studies have shown that HMGB1 activates aortic endothelial cells, increasing the expression of adhesion molecules and the secretion of TNF-α, IL-8 and monocyte chemotactic protein-1 [19]. By these inflammatory effects, HMGB1 is implicated in the pathogenesis of atherosclerosis of aorta and aortic aneurysm [6,20].…”

Section: Introductionmentioning

confidence: 99%

Ectodomain Shedding of RAGE and TLR4 as a Negative Feedback Regulation in High-Mobility Group Box 1-Activated Aortic Endothelial Cells

Yang

Kim

Lee

et al. 2018

Cell Physiol Biochem

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Background/Aims: High-mobility group box 1 (HMGB1) elicits inflammatory responses through interactions with the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). We investigated how RAGE and TLR4 expressions are regulated after HMGB1 stimulation in cultured human aortic endothelial cells (HAECs). Methods: RAGE and TLR4 expressions were analyzed by Western blot analysis and immunofluorescence staining. A disintegrin and metalloprotease 17 (ADAM17) activity was measured using a fluorogenic substrate. Results: Upon treatment with HMGB1, both RAGE and TLR4 began to decrease in cell lysate and remained decreased up to 24 h. The decrease in cellular RAGE and TLR4 was accompanied by an increase of N-terminal fragment of RAGE and TLR4 in culture supernatant, indicating ectodomain shedding of the receptors. HMGB1 activated p38 mitogen-activated protein kinase (p38 MAPK) and ADAM17, while HMGB1-induced ADAM17 activation was inhibited by SB203580, a p38 MAPK inhibitor. HMGB1-induced ectodomain shedding of RAGE and TLR4 was prevented by siRNA depletion of ADAM17 as well as TAPI-2, an inhibitor of ADAM family, and SB203580. HMGB1 pretreatment abolished p38 MAPK activation in response to 2nd HMGB1 stimulation. In the cells depleted of ADAM17, HMGB1-induced p38 MAPK activation was prolonged. siRNA depletion of RAGE, but not TLR4, suppressed HMGB1-induced p38 MAPK activation. Conclusion: In response to HMGB1 stimulation, HAECs rapidly undergo ectodomain shedding of RAGE and TLR4, and thereby become insensitive to further HMGB1 stimulation. ADAM17, activated through RAGE-p38 MAPK pathway, is implicated in the ectodomain cleavage of the receptors.

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Transgenic Expression of Human Thrombomodulin Inhibits HMGB1-Induced Porcine Aortic Endothelial Cell Activation

Cited by 18 publications

References 20 publications

Emerging Role of High Mobility Group Box-1 in Thrombosis-Related Diseases

Emerging Role of High Mobility Group Box-1 in Thrombosis-Related Diseases

Sterile Inflammatory Role of High Mobility Group Box 1 Protein: Biological Functions and Involvement in Disease

Ectodomain Shedding of RAGE and TLR4 as a Negative Feedback Regulation in High-Mobility Group Box 1-Activated Aortic Endothelial Cells

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