Inhibition of Homophilic Interactions and Ligand Binding of the Receptor for Advanced Glycation End Products by Heparin and Heparin-Related Carbohydrate Structures

Rouhiainen, Ari; Nykänen, Niko-Petteri; Kuja-Panula, Juha; Vanttola, Päivi; Huttunen, Henri J.; Rauvala, Heikki

doi:10.3390/medicines5030079

Cited by 4 publications

(5 citation statements)

References 57 publications

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“…Heparin is a high affinity HMGB1-binding molecule (Ling et al 2011;Li et al 2015;Rouhiainen et al 2018). The conformation of HMGB1 changes when heparin combines with HMGB1 and this change inhibits the binding of HMGB1 to the surface of activated macrophages (Ling et al 2011).…”

Section: Heparin and Heparinoid Compoundsmentioning

confidence: 99%

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Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

Andersson

Ottestad

Tracey

2020

Mol Med

204

212

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Background: The 2019 novel coronavirus disease (COVID-19) causes for unresolved reasons acute respiratory distress syndrome in vulnerable individuals. There is a need to identify key pathogenic molecules in COVID-19-associated inflammation attainable to target with existing therapeutic compounds. The endogenous damage-associated molecular pattern (DAMP) molecule HMGB1 initiates inflammation via two separate pathways. Disulfide-HMGB1 triggers TLR4 receptors generating pro-inflammatory cytokine release. Extracellular HMGB1, released from dying cells or secreted by activated innate immunity cells, forms complexes with extracellular DNA, RNA and other DAMP or pathogen-associated molecular (DAMP) molecules released after lytic cell death. These complexes are endocytosed via RAGE, constitutively expressed at high levels in the lungs only, and transported to the endolysosomal system, which is disrupted by HMGB1 at high concentrations. Danger molecules thus get access to cytosolic proinflammatory receptors instigating inflammasome activation. It is conceivable that extracellular SARS-CoV-2 RNA may reach the cellular cytosol via HMGB1-assisted transfer combined with lysosome leakage. Extracellular HMGB1 generally exists in vivo bound to other molecules, including PAMPs and DAMPs. It is plausible that these complexes are specifically removed in the lungs revealed by a 40% reduction of HMGB1 plasma levels in arterial versus venous blood. Abundant pulmonary RAGE expression enables endocytosis of danger molecules to be destroyed in the lysosomes at physiological HMGB1 levels, but causing detrimental inflammasome activation at high levels. Stress induces apoptosis in pulmonary endothelial cells from females but necrosis in cells from males.Conclusion: Based on these observations we propose extracellular HMGB1 to be considered as a therapeutic target for COVID-19.

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Section: Heparin and Heparinoid Compoundsmentioning

confidence: 99%

“…The conformation of HMGB1 changes when heparin combines with HMGB1 and this change inhibits the binding of HMGB1 to the surface of activated macrophages (Ling et al 2011). Heparin-HMGB1 complexes are unable to induce RAGE dimerization that is required for the function of RAGE (Rouhiainen et al 2018) (Fig. 2).…”

Section: Heparin and Heparinoid Compoundsmentioning

confidence: 99%

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

Andersson

Ottestad

Tracey

2020

Mol Med

204

212

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“…Heparin is an anticoagulant agent, acts through activation of endogenous anti-thrombin III, has high affinity to the extracellular HMGB (Li et al 2015 ). Binding of heparin to the HMGB, reduces the ability of HMGB to activate RAGE receptors on the activated macrophages (Rouhiainen et al 2018 ). Therefore, heparin mitigates inflammatory reactions that are induced through HMGB/RAGE receptors axis.…”

Section: Extracellular Hmgb1 Inhibitorsmentioning

confidence: 99%

High-mobility group box 1 (HMGB1) in COVID-19: extrapolation of dangerous liaisons

et al. 2022

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High-mobility group box 1 (HMGB1), a multifunctional nuclear protein, exists mainly within the nucleus of all mammal eukaryotic cells. It is actively secreted by the necrotic cells as a response to the inflammatory signaling pathway. HMGB1 binds to receptor ligands as RAGE, and TLR and becomes a pro-inflammatory cytokine with a robust capacity to trigger inflammatory response. It is a critical mediator of the pathogenesis of systemic inflammation in numerous inflammatory disorders. Release of HMGB1 is associated with different viral infections and strongly participates in the regulation of viral replication cycles. In COVID-19 era, high HMGB1 serum levels were observed in COVID-19 patients and linked with the disease severity, development of cytokine storm (CS), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). SARS-CoV-2-induced cytolytic effect may encourage release of HMGB1 due to nuclear damage. Besides, HMGB1 activates release of pro-inflammatory cytokines from immune cells and up-regulation of angiotensin I-converting enzyme 2 (ACE2). Therefore, targeting of the HMGB1 pathway by anti-HMGB1 agents, such as heparin, resveratrol and metformin, may decrease COVID-19 severity. HMGB1 signaling pathway has noteworthy role in the pathogenesis of SARS-CoV-2 infections and linked with development of ALI and ARDS in COVID-19 patients. Different endogenous and exogenous agents may affect release and activation of HMGB1 pathway. Targeting of HMGB1-mediated TLR2/TLR4, RAGE and MAPK signaling, might be a new promising drug candidate against development of ALI and/or ARDS in severely affected COVID-19 patients.

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“…Heparin also binds Mac-1 and tends to impede the binding of soluble and cell surface ligands to Mac-1 ( 116 ). Although the effects of heparin on RAGE binding to Mac-1 have not been fully explored, heparin does antagonize RAGE dimerization ( 117 ) and binding to the ligand HMGB1 ( 118 ).…”

Section: Macrophage Antigen-1 (Mac-1)mentioning

confidence: 99%

RAGE pathway activation and function in chronic kidney disease and COVID-19

Curran

Kopp

2022

Front. Med.

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The multi-ligand receptor for advanced glycation end-products (RAGE) and its ligands are contributing factors in autoimmunity, cancers, and infectious disease. RAGE activation is increased in chronic kidney disease (CKD) and coronavirus disease 2019 (COVID-19). CKD may increase the risk of COVID-19 severity and may also develop in the form of long COVID. RAGE is expressed in essentially all kidney cell types. Increased production of RAGE isoforms and RAGE ligands during CKD and COVID-19 promotes RAGE activity. The downstream effects include cellular dysfunction, tissue injury, fibrosis, and inflammation, which in turn contribute to a decline in kidney function, hypertension, thrombotic disorders, and cognitive impairment. In this review, we discuss the forms and mechanisms of RAGE and RAGE ligands in the kidney and COVID-19. Because various small molecules antagonize RAGE activity in animal models, targeting RAGE, its co-receptors, or its ligands may offer novel therapeutic approaches to slowing or halting progressive kidney disease, for which current therapies are often inadequate.

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Inhibition of Homophilic Interactions and Ligand Binding of the Receptor for Advanced Glycation End Products by Heparin and Heparin-Related Carbohydrate Structures

Cited by 4 publications

References 57 publications

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

High-mobility group box 1 (HMGB1) in COVID-19: extrapolation of dangerous liaisons

RAGE pathway activation and function in chronic kidney disease and COVID-19

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