Inhibition of peptidyl arginine deiminase-4 protects against myocardial infarction induced cardiac dysfunction

Du, Mingjun; Yang, Wengang; Schmull, Sebastian; Gu, Jianmin; Xue, Song

doi:10.1016/j.intimp.2019.106055

Cited by 62 publications

(46 citation statements)

References 33 publications

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“…Further investigations have revealed PAD4-mediated citrullination of certain proteins in several innate immunity and autoimmune diseases, such as colitis, lupus, rheumatoid arthritis, and multiple sclerosis [ 28 , 29 ]. In recent years, PAD4 has attracted increasing attention due to its critical role in ischemic injury in various tissues, including the kidney and heart [ 16 , 30 , 31 ]. The PAD4 protein is barely expressed under normal conditions but can be activated in various tissues under pathological conditions [ 32 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…GSK484 (4 mg/kg) was administered daily by intraperitoneal injection for 3 days before the operation. GSK484 was initially dissolved in 99.9% ethanol at a concentration of 25 mg/mL to generate a stock solution and then diluted 1 : 50 in sterile saline before injection (200 μ L/mouse) [ 16 , 20 ]. The vehicle was prepared in the same way as GSK484 solution except GSK484 was omitted.…”

Section: Methodsmentioning

confidence: 99%

“…PAD4 is regarded as a major regulator of NET formation via citrullination of histone H3 (CitH3), which leads to chromatin decondensation and release [ 3 ]. Furthermore, PAD4-mediated peptidyl citrullination is increased in several autoimmune and ischemic diseases, such as rheumatoid arthritis, multiple sclerosis, and myocardial infarction [ 16 , 17 ]. Recent reports indicate that PAD4 activation contributes to acute tissue damage by directly exacerbating the inflammatory response [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…GSK484 hydrochloride ([(3S,4R)-3-amino-4-hydroxy-1-piperidinyl] [2-[1-(cyclopropylmethyl)-1H-indol-2-yl]-7-methoxy-1-methyl-1Hbenzimidazol-5-yl]-methanone), a selective PAD4 inhibitor, has been used as an anti-ischemic compound and exerts inhibitory activity against PAD4 [ 16 , 19 ]. We hypothesize that GSK484 could serve as an anti-ischemic reagent by inhibiting PAD4 and downstream responses of tissues to IR.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Peptidyl Arginine Deiminase-4 Prevents Renal Ischemia-Reperfusion-Induced Remote Lung Injury

Yang

et al. 2020

Mediators of Inflammation

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Ischemia reperfusion (IR) can lead to acute kidney injury and can be complicated by acute lung injury, which is one of the leading causes of acute kidney injury-related death. Peptidyl arginine deiminase-4 (PAD4) is a member of the PAD enzyme family and plays a critical role in inflammatory reactions and neutrophil extracellular trap formation in a variety of pathological conditions. It has been reported that PAD4 inhibition can protect certain organs from ischemic injury. In this study, we aimed to understand the mode of action of PAD4 in renal ischemia-reperfusion-mediated acute lung injury. Bilateral renal pedicle occlusion was induced for 30 min followed by reperfusion for 24 h. A specific inhibitor of PAD4, GSK484, was delivered via intraperitoneal injection to alter the PAD4 activity. The pulmonary PAD4 expression, pulmonary impairment, neutrophil infiltration, Cit-H3 expression, neutrophil extracellular trap formation, inflammatory cytokine secretion, and pulmonary apoptosis were analyzed. We found that renal ischemia reperfusion was associated with pulmonary pathological changes and increases in neutrophil infiltration, neutrophil extracellular trap formation, and inflammatory cytokine secretion in the lungs of the recipient animals. Suppression of PAD4 by GSK484 reduced remote lung injury by mitigating neutrophil infiltration, neutrophil extracellular trap formation, apoptosis, and inflammatory factor secretion. Our findings demonstrate that specific PAD4 inhibition by GSK484 may be an effective strategy to attenuate distant lung injury complicating renal ischemia-reperfusion injury.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of Peptidyl Arginine Deiminase-4 Prevents Renal Ischemia-Reperfusion-Induced Remote Lung Injury

Yang

et al. 2020

Mediators of Inflammation

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“…In fact, increased concentrations of extracellular PAD4 have been found in the plasma of patients with rheumatoid arthritis (RA) [ 119 ], multiple sclerosis [ 120 ], Alzheimer’s disease [ 121 ], sepsis [ 122 ] and malignant tumors [ 123 ]. Additionally, mitigation of disease severity due to PAD4 deficiency or by treatment with PAD inhibitors was reported in mouse models of RA [ 123 , 124 ], hypoxic ischemic insult in neonates [ 125 ], cardiac dysfunction [ 126 ] and neurodegenerative disorders [ 120 ]. It is important to note that PAD4 deficient mice not only failed to produce citrullinated histones in thrombi but were also unable to form stable thrombi in deep vein thrombosis, suggesting the importance of PAD4 in NET-thrombosis interaction [ 127 ].…”

Section: Pad4 In the Crosstalk Between Netosis And Thrombosis In Cmentioning

confidence: 99%

Role of HMGB1 in the Interplay between NETosis and Thrombosis in Ischemic Stroke: A Review

Kim

Lee

2020

Cells

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Neutrophil extracellular traps (NETs) comprise decondensed chromatin, histones and neutrophil granular proteins and are involved in the response to infectious as well as non-infectious diseases. The prothrombotic activity of NETs has been reported in various thrombus-related diseases; this activity can be attributed to the fact that the NETs serve as a scaffold for cells and numerous coagulation factors and stimulate fibrin deposition. A crosstalk between NETs and thrombosis has been indicated to play a role in numerous thrombosis-related conditions including stroke. In cerebral ischemia, neutrophils are the first group of cells to infiltrate the damaged brain tissue, where they produce NETs in the brain parenchyma and within blood vessels, thereby aggravating inflammation. Increasing evidences suggest the connection between NETosis and thrombosis as a possible cause of “tPA resistance”, a problem encountered during the treatment of stroke patients. Several damage-associated molecular pattern molecules have been proven to induce NETosis and thrombosis, with high mobility group box 1 (HMGB1) playing a critical role. This review discusses NETosis and thrombosis and their crosstalk in various thrombosis-related diseases, focusing on the role of HMGB1 as a mediator in stroke. We also addresses the function of peptidylarginine deiminase 4 with respect to the interplay with HMGB1 in NET-induced thrombosis.

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Engineering Injectable Anti‐Inflammatory Hydrogels to Treat Acute Myocardial Infarction

Zhang

Liu

2022

Advanced NanoBiomed Research

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Acute myocardial infarction (AMI) poses serious threats to human health. Suppressing long-term inflammation is a promising strategy to improve cardiac function following AMI. However, the direct injection of anti-inflammatory drugs after AMI can trigger adverse events due to systemic off-target effects and bioavailability issues. Injectable hydrogels can be used for local transportation of various therapeutic molecules through minimally invasive technology to overcome the side effects of intravenous injection. Herein, the anti-inflammatory mechanisms and applications of injectable hydrogels are reviewed to deliver antiinflammatory drugs, antioxidants, immune-regulation drugs, stem cells and their derived exosomes, and therapeutic gas to reduce the inflammatory response to treat AMI. The outlook on challenges in the design of hydrogels for treating AMI is also presented.

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Inhibition of peptidyl arginine deiminase-4 protects against myocardial infarction induced cardiac dysfunction

Cited by 62 publications

References 33 publications

Inhibition of Peptidyl Arginine Deiminase-4 Prevents Renal Ischemia-Reperfusion-Induced Remote Lung Injury

Inhibition of Peptidyl Arginine Deiminase-4 Prevents Renal Ischemia-Reperfusion-Induced Remote Lung Injury

Role of HMGB1 in the Interplay between NETosis and Thrombosis in Ischemic Stroke: A Review

Engineering Injectable Anti‐Inflammatory Hydrogels to Treat Acute Myocardial Infarction

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