scholarly journals P2X7 Receptor–Mediated Inflammation in Cardiovascular Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Junteng Zhou ◽  
Zhichao Zhou ◽  
Xiaojing Liu ◽  
Hai-Yan Yin ◽  
Yong Tang ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Cardiovascular Diseases ◽  
P2x7 Receptor ◽  
Cardiac Fibrosis ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Experimental Studies ◽  
Therapeutic Interventions ◽  
Receptor Protein ◽  
Inflammasome Activation

Purinergic P2X7 receptor, a nonselective cation channel, is highly expressed in immune cells as well as cardiac smooth muscle cells and endothelial cells. Its activation exhibits to mediate nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome activation, resulting in the release of interleukin-1 beta (IL-1β) and interleukin-18 (IL-18), and pyroptosis, thus triggering inflammatory response. These pathological mechanisms lead to the deterioration of various cardiovascular diseases, including atherosclerosis, arrhythmia, myocardial infarction, pulmonary vascular remodeling, and cardiac fibrosis. All these worsening cardiac phenotypes are proven to be attenuated after the P2X7 receptor inhibition in experimental studies. The present review aimed to summarize key aspects of P2X7 receptor–mediated inflammation and pyroptosis in cardiovascular diseases. The main focus is on the evidence addressing the involvement of the P2X7 receptor in the inflammatory responses to the occurrence and development of cardiovascular disease and therapeutic interventions.

scholarly journals NLRP3 Inflammasome Activation Enhanced by TRIM25 is Targeted by the NS1 Protein of 2009 Pandemic Influenza A Virus

2021 ◽  
Vol 12 ◽  
Author(s):  
Hong-Su Park ◽  
Yao Lu ◽  
Kannupriya Pandey ◽  
GuanQun Liu ◽  
Yan Zhou
Keyword(s):  
Influenza A Virus ◽  
Nlrp3 Inflammasome ◽  
Influenza A ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Inflammasome Activation ◽  
Ns1 Protein ◽  
Structural Protein ◽  
Caspase 1 ◽  
C Terminus

Nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome-mediated interleukin-1 beta (IL-1β) production is one of the crucial responses in innate immunity upon infection with viruses including influenza A virus (IAV) and is modulated by both viral and host cellular proteins. Among host proteins involved, we identified tripartite motif-containing protein 25 (TRIM25) as a positive regulator of porcine NLRP3 inflammasome-mediated IL-1β production. TRIM25 achieved this function by enhancing the pro-caspase-1 interaction with apoptosis-associated speck-like protein containing caspase recruitment domain (ASC). The N-terminal RING domain, particularly residues predicted to be critical for the E3 ligase activity of TRIM25, was responsible for this enhancement. However, non-structural protein 1 (NS1) C-terminus of 2009 pandemic IAV interfered with this action by interacting with TRIM25, leading to diminished association between pro-caspase-1 and ASC. These findings demonstrate that TRIM25 promotes the IL-1β signaling, while it is repressed by IAV NS1 protein, revealing additional antagonism of the NS1 against host pro-inflammatory responses.

scholarly journals Resveratrol Suppresses Gut-Derived NLRP3 Inflammasome Partly through Stabilizing Mast Cells in a Rat Model

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Weicheng Zhao ◽  
Xiaolei Huang ◽  
Xue Han ◽  
Dan Hu ◽  
Xiaohuai Hu ◽  
...  
Keyword(s):  
Mast Cells ◽  
Proinflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Intestinal Ischemia ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Interleukin 1 ◽  
Intestinal Injury ◽  
Cromolyn Sodium ◽  
Inflammasome Activation

Background. Inflammatory responses induced by intestinal ischemia-reperfusion (IIR) lead to serious systemic organ dysfunction and pose a challenge for current treatment. This study aimed at investigating the effects of resveratrol on IIR-induced intestinal injury and its influence on mast cells (MCs) in rats. Methods. Rats subjected to intestinal ischemia for 60 min and 4 h of IIR were investigated. Animals were randomly divided into five groups (n=8 per group): sham, IIR, resveratrol (RESV, 15 mg/kg/day for 5 days before operation) + IIR, cromolyn sodium (CS, MC membrane stabilizer) + IIR, and RESV + compound 48/80 (CP, MC agonist) + IIR. Results. Intestinal injury and increased proinflammatory cytokines including tumor necrosis factor-α, interleukin-1β, and interleukin-18 were observed in the IIR group. Intestinal MC-related tryptase and β-hexosaminidase levels were also increased after rats were subjected to IIR accompanied by activation of NLRP3 inflammasomes. Interestingly, pretreatment with resveratrol significantly suppressed the activities of proinflammatory cytokines and attenuated intestinal injury. Resveratrol also reduced MC and NLRP3 inflammasome activation, which was consistent with the effects of cromolyn sodium. However, the protective effects of resveratrol were reversed by the MC agonist compound 48/80. Conclusions. In summary, these findings reveal that resveratrol suppressed IIR injury by stabilizing MCs, preventing them from degranulation, accompanied with intestinal mucosa NLRP3 inflammasome inhibition and intestinal epithelial cell apoptosis reduction.

Cordycepin inhibits LPS-induced inflammatory responses by modulating NOD-Like Receptor Protein 3 inflammasome activation

2017 ◽  
Vol 95 ◽  
pp. 1777-1788 ◽  
Author(s):  
Jing Yang ◽  
Yun-zhou Li ◽  
Phillip B. Hylemon ◽  
Lu-yong Zhang ◽  
Hui-ping Zhou
Keyword(s):  
Inflammatory Responses ◽  
Receptor Protein ◽  
Inflammasome Activation

scholarly journals Dual Role of Triptolide in Interrupting the NLRP3 Inflammasome Pathway to Attenuate Cardiac Fibrosis

2019 ◽  
Vol 20 (2) ◽  
pp. 360 ◽  
Author(s):  
Xi-Chun Pan ◽  
Ya Liu ◽  
Yan-Yan Cen ◽  
Ya-Lan Xiong ◽  
Jing-Mei Li ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Dual Role ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Collagen Production ◽  
Antifibrotic Effect ◽  
Myeloid Differentiation Factor

In a previous paper, we reported that triptolide (TP), a commonly used immunomodulator, could attenuate cardiac hypertrophy. This present study aimed to further explore the inhibition of cardiac fibrosis by TP and the possible mechanism from the perspective of the NOD-like receptor protein 3 (NLRP3) inflammasome. Hematoxylin-eosin and Masson’s staining, immunohistochemistry, and immunofluorescence were performed to observe cardiac fibrotic changes in mice and mouse cardiac fibroblasts (CFs). The Western blot, colocalization, and immunoprecipitation were applied to detect protein expression and interactions. Results suggested that TP dose-dependently inhibited cardiac fibrosis induced by isoproterenol and collagen production of CFs induced by angiotensin II. TP exhibited an antifibrotic effect via inhibiting activation of the NLRP3 inflammasome, which sequentially decreased IL-1β maturation, myeloid differentiation factor 88 (MyD88)-related phosphorylation of c-Jun N-terminal kinase (JNK), extracellular regulated protein kinase 1/2 (ERK1/2), and TGF-β1/Smad signaling, and ultimately resulted in less collagen production. Moreover, TP showed no antifibrotic effect in Nlrp3-knockout CFs. Notably, TP inhibited the expression of NLRP3 and apoptosis-associated speck-like proteins containing a caspase recruitment domain (ASC) as well as inflammasome assembly, by interrupting the NLRP3-ASC interaction to inhibit inflammasome activation. Finally, TP indeed inhibited the NLRP3-TGFβ1-Smad pathway in vivo. Conclusively, TP was found to play a dual role in interrupting the activation of the NLRP3 inflammasome to attenuate cardiac fibrosis.

More purinergic receptors deserve attention as therapeutic targets for the treatment of cardiovascular disease

2020 ◽  
Vol 319 (4) ◽  
pp. H723-H729 ◽  
Author(s):  
Bernhard Wernly ◽  
Zhichao Zhou (周稚超)
Keyword(s):  
Cardiovascular Disease ◽  
Cardiovascular Diseases ◽  
Purinergic Receptors ◽  
Treatment Options ◽  
Experimental Studies ◽  
Therapeutic Targets ◽  
Independent Effect ◽  
Coronary Syndrome ◽  
Future Drug ◽  
New Treatment

Cardiovascular disease is a major cause of morbidity and mortality worldwide. Innovative new treatment options for this cardiovascular pandemic are urgently needed. Activation of purinergic receptors (PRs) is critically involved in the development and progression of cardiovascular disease including atherosclerosis, ischemic heart disease, hypertension, and diabetes. PRs have been targeted for the treatment of several cardiovascular diseases in a clinical setting. The P2Y12R antagonists such as clopidogrel, ticagrelor, and others are the most successful class of purinergic drugs targeting platelets for the treatment of acute coronary syndrome. In addition to targeting platelets, ticagrelor may exert P2Y12R-independent effect by targeting erythrocyte-mediated purinergic activation. The partial A1R agonist neladenoson and the A2AR agonist regadenoson have been applied in cardiovascular medicine. In experimental studies, many other PRs have been shown to play a significant role in the development and progression of cardiovascular diseases, and targeting these receptors have resulted in promising outcomes. Therefore, many of these PRs including A2BR, A3R, P2X3R, P2X4R, P2X7R, P2Y1R, P2Y4R, P2Y6R, and P2Y11R can be considered as therapeutic targets. However, the multitude of PR subtypes expressed in different cells of the cardiovascular system may constitute a challenge whether single or multiple receptors should be targeted at the same time for the best efficacy. The present review discusses the promising purinergic drugs used in clinical studies for the treatment of cardiovascular disease. We also update experimental evidence for many other PRs that can be considered as therapeutic targets for future drug development.

End-organ dysfunction and cardiovascular outcomes: the role of the microcirculation

2009 ◽  
Vol 116 (3) ◽  
pp. 175-190 ◽  
Author(s):  
Christopher J. Lockhart ◽  
Paul K. Hamilton ◽  
Cathy E. Quinn ◽  
Gary E. McVeigh
Keyword(s):  
Cardiovascular Disease ◽  
Organ Dysfunction ◽  
Inflammatory Responses ◽  
Structure And Function ◽  
Therapeutic Interventions ◽  
Pivotal Role ◽  
Vascular Effects ◽  
Microvascular Damage ◽  
Arterial Blood ◽  
And Function

Risk factors for cardiovascular disease mediate their effects by altering the structure and function of wall and endothelial components of arterial blood vessels. A pathological change in the microcirculation plays a pivotal role in promoting end-organ dysfunction that not only predisposes to further organ damage, but also increases the risk for future macrovascular events. The microcirculation is recognized as the site where the earliest manifestations of cardiovascular disease, especially inflammatory responses, occur that may play a pivotal role in driving the atherosclerotic process in conduit vessels. Furthermore, the vast surface area of the endothelium compared with conduit vessels means that the vascular effects of endothelial dysfunction or activation will be most apparent in this section of the vasculature. Current techniques providing indices of vascular health focus on large arteries without providing insight into the structure and function of small vessels. Techniques capable of detecting microvascular damage and monitoring the response to therapeutic interventions, especially in vulnerable target organs of interest, may improve risk stratification and represent a valuable surrogate for future cardiovascular outcome.

scholarly journals Anakinra Activates Superoxide Dismutase 2 to Mitigate Inflammasome Activity

2021 ◽  
Vol 22 (12) ◽  
pp. 6531
Author(s):  
Marilena Pariano ◽  
Stefania Pieroni ◽  
Antonella De Luca ◽  
Rossana G. Iannitti ◽  
Monica Borghi ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Inflammasome Activation ◽  
Mitochondrial Oxidative Stress ◽  
Pyrin Domain ◽  
Mitochondrial Ros ◽  
Activation Of Transcription ◽  
Superoxide Dismutase 2 ◽  
Nlrp3 Activity

Inflammasomes are powerful cytosolic sensors of environmental stressors and are critical for triggering interleukin-1 (IL-1)-mediated inflammatory responses. However, dysregulation of inflammasome activation may lead to pathological conditions, and the identification of negative regulators for therapeutic purposes is increasingly being recognized. Anakinra, the recombinant form of the IL-1 receptor antagonist, proved effective by preventing the binding of IL-1 to its receptor, IL-1R1, thus restoring autophagy and dampening NLR family pyrin domain containing 3 (NLRP3) activity. As the generation of mitochondrial reactive oxidative species (ROS) is a critical upstream event in the activation of NLRP3, we investigated whether anakinra would regulate mitochondrial ROS production. By profiling the activation of transcription factors induced in murine alveolar macrophages, we found a mitochondrial antioxidative pathway induced by anakinra involving the manganese-dependent superoxide dismutase (MnSOD) or SOD2. Molecularly, anakinra promotes the binding of SOD2 with the deubiquitinase Ubiquitin Specific Peptidase 36 (USP36) and Constitutive photomorphogenesis 9 (COP9) signalosome, thus increasing SOD2 protein longevity. Functionally, anakinra and SOD2 protects mice from pulmonary oxidative inflammation and infection. On a preclinical level, anakinra upregulates SOD2 in murine models of chronic granulomatous disease (CGD) and cystic fibrosis (CF). These data suggest that protection from mitochondrial oxidative stress may represent an additional mechanism underlying the clinical benefit of anakinra and identifies SOD2 as a potential therapeutic target.

scholarly journals Cytokine storms and pyroptosis are primarily responsible for the rapid death of mice infected with pseudorabies virus

2021 ◽  
Vol 8 (8) ◽  
pp. 210296
Author(s):  
Wei Sun ◽  
Shanshan Liu ◽  
Xuefei Huang ◽  
Rui Yuan ◽  
Jiansheng Yu
Keyword(s):  
Pseudorabies Virus ◽  
Immune Reaction ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Clinical Manifestations ◽  
Receptor Protein ◽  
Tnf Α ◽  
Pathogenesis Related ◽  
Hematoxylin Eosin ◽  
Pro Inflammatory Cytokines

Pseudorabies virus (PRV), the causative agent of Aujeszky's disease, is one of the most harmful pathogens to the pig industry. PRV can infect and kill a variety of mammals. Nevertheless, the underlying pathogenesis related to PRV is still unclear. This study aims to investigate the pathogenesis induced by PRV in a mouse model. The mice infected with the PRV-HLJ strain developed severe clinical manifestations at 36 h post-infection (hpi), and mortality occurred within 48–72 hpi. Hematoxylin-eosin staining and qRT-PCR methods were used to detect the pathological damage and expression of cytokines related to an immune reaction in brain tissue, respectively. The cytokine storms caused by IFN-α, IFN- β , TNF-α, IL-1 β , IL-6 and IL-18 were related to the histopathological changes induced by PRV. This pattern of cytokine secretion depicts an image of typical cytokine storms, characterized by dysregulated secretion of pro-inflammatory cytokines and imbalanced pro-inflammatory and anti-inflammatory responses. In addition, the pyroptosis pathway was also activated by PRV by elevating the expression levels of nod-like receptor protein 3, Caspase-1, Gasdermin-D and interleukin-1 β /18. These findings provide a way for further understanding the molecular basis in PRV pathogenesis.

scholarly journals Orientin Ameliorates LPS-Induced Inflammatory Responses through the Inhibitory of the NF-κB Pathway and NLRP3 Inflammasome

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Qingfei Xiao ◽  
Zhihui Qu ◽  
Ying Zhao ◽  
Liming Yang ◽  
Pujun Gao
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Receptor Protein ◽  
Raw 264.7 Cells ◽  
Prostaglandin E ◽  
Inflammasome Activation ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Nlrp3 Inflammasome Activation ◽  
Underlying Mechanisms

Inflammation is a complex response to diverse pathological conditions, resulting in negative rather than protective effects when uncontrolled. Orientin (Ori), a flavonoid component isolated from natural plants, possesses abundant properties. Thus, we aimed to discover the potential therapeutic effects of orientin on lipopolysaccharide- (LPS-) induced inflammation in RAW 264.7 cells and the underlying mechanisms. In our studies, we evaluated the effects of Ori on proinflammatory mediator production stimulated by LPS, including tumor necrosis factor- (TNF-) α, interleukin- (IL-) 6, IL-18, and IL-1β, along with prostaglandin E2 (PGE2) and NO. Our data indicated that orientin dramatically inhibited the levels of these mediators. Consistent with these results, the expression levels of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were also reduced. Further study demonstrated that such inhibitory effects of Ori were due to suppression of the nuclear factor-kappa B (NF-κB) pathway and nucleotide-binding domain- (NOD-) like receptor protein 3 (NLRP3) inflammasome activation, which may contribute to its anti-inflammatory effects. Together, these findings show that Ori may be an effective candidate for ameliorating LPS-induced inflammatory responses.

A Crucial Role for Caspase 1 in Thrombo-Inflammatory Microparticle Release

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2806-2806
Author(s):  
Andrea S Rothmeier ◽  
Patrizia Marchese ◽  
Christian Furlan-Freguia ◽  
Brian G. Petrich ◽  
Mark H. Ginsberg ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Cell Surface ◽  
P2x7 Receptor ◽  
Receptor Activation ◽  
Common Mechanism ◽  
Inflammasome Activation ◽  
Disulfide Exchange ◽  
Phalloidin Staining ◽  
Cytoskeletal Remodeling ◽  
Caspase 1

Abstract Macrophages are central orchestrators in the detrimental cycle of inflammation and coagulation in cardiovascular diseases. Cell injury signals trigger the macrophages P2X7 receptor and thereby induce the release both proinflammatory IL-1β and prothrombotic MP. Prothrombotic MP carry tissue factor (TF) and high content of phosphatidylserine (PS), and can induce thrombosis causing major clinical complications in patients. We previously identified the P2X7 receptor as a crucial component of thrombosis in mice, but the mechanistic details of macrophage MP release in this thrombo-inflammatory pathway remain incompletely understood. The the generation of these MP requires thiol-disulfide exchange-dependent activation of the inflammasome and is accompanied by the release of various soluble proteins into the extracellular space. We hypothesized that the released proteome presents regulators and structural components of the MP generation pathway and employed proteomics to unveil their identity. Amongst the most abundant proteins were γ-actin and actin cytoskeleton associated proteins, including PS-binding proteins annexin 1 and annexin 5. Cytoskeletal remodeling processes leading to formation of filopodia downstream of P2X7 receptor activation were crucial for the biogenesis of thrombo-inflammatory MP, since pharmacological inhibitors of inflammasome activation, cytoskeletal remodeling and the thioredoxin system attenuated both, filopodia formation and the release of highly procoagulant MP. Confocal microscopy demonstrated raft dependent translocation of TF onto filopodia that was prevented by the same inhibitory strategies. Surprisingly, phalloidin-staining of non-permeabilized macrophages revealed that F-actin is exposed to the cell surface decorating the base of filopodia. Positive phalloidin-staining of thrombo-inflammatory MP further demonstrated that F-actin remained associated with the MP surface. Strikingly, blocking surface actin by incubation with high concentration of phalloidin prevented the release of PS-rich MP, demonstrating that exposure of F-actin during filopodia formation is functionally linked to the biogenesis of thrombo-inflammatory MP. As the underlying common mechanism for thiol-disulfide exchange-dependent cell surface actin exposure and MP release, we showed that blockade of the cysteine protease caspase 1, which mediates processing and release of IL-1β downstream of inflammasome activation is also required for the release of thrombo-inflammatory MP. Although caspase 1-mediated activation of caplain was required for the release of filamin A localized TF to the cell cortex, calpain was not involved in the release of thrombo-inflammatory MP release. The N-terminus of γ-actin harbors a recognition and cleavage motif for caspase 1. Residual γ-actin released from caspase 1-blocked macrophages showed decreased electrophoretic mobility, indicating prior cleavage of actin that becomes exposed on the cell surface. We show here that the proteome released during thrombo-inflammatory activation of macrophages includes critical players in the biogenesis of MP and may provide diagnostic fingerprints in complex biological samples. Our data demonstrate an entirely unexpected role for caspase 1 and surface exposure of polymerized actin in the severing of prothrombotic MP from filopodia and thus position this protease upstream of both IL-1β processing and thrombo-inflammatory MP in cardiovascular diseases. Disclosures No relevant conflicts of interest to declare.

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