The Role of HMGB1 in Cardiovascular Biology: Danger Signals

Cai, Jingjing; Wen, Juan; Bauer, Eileen; Zhong, Hua; Yuan, Hong; Chen, Alex F.

doi:10.1089/ars.2015.6408

Cited by 64 publications

(64 citation statements)

References 208 publications

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“…Thus, future studies should pay particular attention to exploring these mechanisms in detail. Recently, some approaches have been shown to be protective in models of vascular pathologies at least in part, via inhibiting HMGB1 expression, release, or activity [39, 138-140]. With more clues uncovered, other approaches to preventing HMGB1 release or binding to its receptors will provide novel strategies for treating cardiovascular calcification and reducing cardiovascular events.…”

Section: Discussionmentioning

confidence: 99%

“…The role of HMGB1 has been investigated in several systemic disorders, including sepsis, cancer, kidney diseases [36], thrombosis [37, 38], and certain autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) [9, 33, 34]. HMGB1 is also a critical mediator in vascular diseases [39] such as atherosclerosis [35, 40, 41], myocardial ischemia/reperfusion (I/R) injury [42, 43], heart failure [44, 45], acute coronary syndrome (ACS) [46, 47], vasculitis [34], pulmonary artery disease [48-50], cerebral artery disease [51-53], and peripheral artery diseases (PADs) [54, 55]. …”

Section: The Basic Actions Of Hmgb1mentioning

confidence: 99%

“…When released into the extracellular space upon cell activation, injury or death, HMGB1 functions as a damage-associated molecular pattern (DAMP) [11], and extracellular HMGB1 has drawn increasing attention with regard to its involvement in the pathogenesis of autoimmune and inflammatory diseases [12-14]. HMGB1 is also known as a bone-active cytokine that participates in both bone remodeling and ectopic calcification pathogenesis [15, 16].…”

Section: Introductionmentioning

confidence: 99%

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Roles of High Mobility Group Box 1 in Cardiovascular Calcification

Chen¹,

Wang²,

Chen³

et al. 2017

Cell Physiol Biochem

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Calcific disease of the cardiovascular system, including atherosclerotic calcification, medial calcification in diabetes and calcific aortic valve disease, is an important risk factor for many adverse cardiovascular events such as ischemic cardiac events and subsequent mortality. Although cardiovascular calcification has long been considered to be a passive degenerative occurrence, it is now recognized as an active and highly regulated process that involves osteochondrogenic differentiation, apoptosis and extracellular vesicle release. Nonetheless, despite numerous studies on the pathogenesis of cardiovascular calcification, the underlying mechanisms remain poorly understood. High mobility group box 1 (HMGB1), a nuclear protein bound to chromatin in almost all eukaryotic cells, acts as a damage-associated molecular pattern (DAMP) when released into the extracellular space upon cell activation, injury or death. Moreover, HMGB1 also functions as a bone-active cytokine participating in bone remodeling and ectopic calcification pathogenesis. However, studies on the roles of HMGB1 in promoting cardiovascular calcification are limited to date, and the mechanisms involved are still unclear. In this review, we summarize recent studies investigating the mechanism of cardiovascular calcification and discuss multiple roles of HMGB1 in its development.

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Section: Discussionmentioning

confidence: 99%

Section: The Basic Actions Of Hmgb1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Roles of High Mobility Group Box 1 in Cardiovascular Calcification

Chen¹,

Wang²,

Chen³

et al. 2017

Cell Physiol Biochem

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“…vascular IH (12). Infiltration of inflammatory cells including monocytes/macrophages is the initial event of the vascular inflammatory response (28). Some essential proinflammatory mediators, such as cytokines, chemokines and adhesion molecules, recruit inflammatory cells into the vascular wall and propagate the inflammatory response for the formation of IH.…”

Section: Saquinavir Inhibits Cathepsin L Activity and Intimal Hyperplmentioning

confidence: 99%

“…Some essential proinflammatory mediators, such as cytokines, chemokines and adhesion molecules, recruit inflammatory cells into the vascular wall and propagate the inflammatory response for the formation of IH. TLR4 activation by endogenous agonist like HMGB1, released by injured or necrotic cells, has been implicated in the pathogenesis of injury-driven disorders such as atherosclerosis and restenosis (12,(28)(29)(30). The TLR4/MD2 receptor complex utilizes the adapter molecule MyD88 and TIR domain-containing adapter-inducing interferon-β signaling adapters to induce expression of cytokines and chemokines (31).…”

Section: Saquinavir Inhibits Cathepsin L Activity and Intimal Hyperplmentioning

confidence: 99%

Cathepsin L Promotes Vascular Intimal Hyperplasia after Arterial Injury

Cai

Zhong

et al. 2017

Mol Med

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The inflammatory pathways that drive the development of intimal hyperplasia (IH) following arterial injury are not fully understood. We hypothesized that the lysosomal cysteine protease cathepsin L activates processes leading to IH after arterial injury. Using a mouse model of wire-induced carotid artery injury, we showed that cathepsin L activity peaks at d 7 and remains elevated for 28 d. Genetic deletion of cathepsin L prevented IH and monocyte recruitment in the carotid wall. The injury-induced increases in cathepsin L mRNA and activity were mitigated in mice with myeloid-specific deletion of toll-like receptor 4 (TLR4) or myeloid differentiation primary response gene 88 (MyD88). We further discovered that the HIV protease inhibitor saquinavir (SQV), which is known to block recombinant mouse cathepsin L activity in vitro, prevented IH after arterial injury. SQV also suppressed LPS (TLR4 agonist)-induced monocyte adhesion to endothelial monolayers. These findings establish cathepsin L as a critical regulator of the inflammation that leads to IH and that the TLR4-MyD88 pathway in myeloid lineages regulates cathepsin L expression in the vessel wall following wire injury. The Food and Drug Administration-approved drug SQV blocks IH though mechanisms that may include the suppression of cathepsin L.

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Multiple inducers of endothelial NOS (eNOS) dysfunction in sickle cell disease

Hebbel

Vercellotti

2021

American J Hematol

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A characteristic aspect of the robust, systemic inflammatory state in sickle cell disease is dysfunction of endothelial nitric oxide synthase (eNOS). We identify 10 aberrant endothelial cell inputs, present in the specific sickle context, that are known to have the ability to cause eNOS dysfunction. These are: endothelial arginase depletion, asymmetric dimethylarginine, complement activation, endothelial glycocalyx degradation, free fatty acids, inflammatory mediators, microparticles, oxidized low density lipoproteins, reactive oxygen species, and Toll‐like receptor 4 signaling ligands. The effect of true eNOS dysfunction on clinical testing using flow‐mediated dilation can be simulated by two known examples of endothelial dysfunction mimicry (hemoglobin consumption of NO; and oxidation of smooth muscle cell soluble guanylate cyclase). This lends ambiguity to interpretation of such clinical testing. The presence of these multiple perturbing factors argues that a therapeutic approach targeting only a single injurious endothelial input (or either example of mimicry) would not be sufficiently efficacious. This would seem to argue for identifying therapeutics that directly protect eNOS function or application of multiple therapeutic approaches.

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The Role of HMGB1 in Cardiovascular Biology: Danger Signals

Abstract: A key focus for future researches on HMGB1 location, structure, modification, and signaling will reveal HMGB1's multiple functions and discover a targeted therapy that can eliminate HMGB1-mediated inflammation without interfering with adaptive immune responses.

Cited by 64 publications

References 208 publications

Roles of High Mobility Group Box 1 in Cardiovascular Calcification

Roles of High Mobility Group Box 1 in Cardiovascular Calcification

Cathepsin L Promotes Vascular Intimal Hyperplasia after Arterial Injury

Multiple inducers of endothelial NOS (eNOS) dysfunction in sickle cell disease

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