Protease activated receptor 4: a backup receptor or a dark horse as a target in antiplatelet therapy?
Ontology highlight
ABSTRACT:
SUBMITTER: Han X
PROVIDER: S-EPMC5879510 | biostudies-literature | 2018 Feb
REPOSITORIES: biostudies-literature
Publications
Protease activated receptor 4: a backup receptor or a dark horse as a target in antiplatelet therapy?
Annals of translational medicine 20180201 3
Similar Datasets
Project description: Not available
| S-EPMC5788293 | biostudies-literature
Project description:BackgroundPlatelet activation and arterial thrombosis on a ruptured atherosclerotic plaque is a major cause of myocardial infarction. Dual antiplatelet therapy (DAPT), the combination of platelet aggregation inhibitors, aspirin and a P2Y12 antagonist, is used to prevent arterial thrombosis. However, many people continue to have arterial thrombosis and myocardial infarction despite DAPT, indicating that additional therapies are required where DAPT is insufficient.ObjectivesTo determine whether antagonists of protease-activated receptors (PARs) can prevent occlusive thrombosis under conditions where DAPT is insufficient.MethodsWe used human whole blood in a microfluidic model of occlusive thrombosis to compare conditions under which DAPT is effective to those under which DAPT was not. Cangrelor (a P2Y12 antagonist) and aspirin were used to mimic DAPT. We then investigated whether the PAR1 antagonist vorapaxar or the PAR4 antagonist BMS 986120, alone or in combination with DAPT, prevented occlusive thrombosis.Results and conclusionsA ruptured plaque exposes collagen fibers and is often rich in tissue factor, triggering activation of platelets and coagulation. Occlusive thrombi formed on type I collagen in the presence or absence of tissue factor (TF). However, although DAPT prevented occlusive thrombosis in the absence of TF, DAPT had little effect when TF was also present. Under these conditions, PAR antagonism was also ineffective. However, occlusive thrombosis was prevented by combining DAPT with PAR antagonism. These data demonstrate that PAR antagonists may be a useful addition to DAPT in some patients and further demonstrate the utility of in vitro models of occlusive thrombosis.
| S-EPMC9001860 | biostudies-literature
Project description:Pancreatic cancer is one of the deadliest malignant tumors, which is a serious threat to human health and life, and it is expected that pancreatic cancer may be the second leading cause of cancer death in developed countries by 2030. Claudin18.2 is a tight junction protein expressed in normal gastric mucosal tissues, which is involved in the formation of tight junctions between cells and affects the permeability of paracellular cells. Claudin18.2 is highly expressed in pancreatic cancer and is associated with the initiation, progression, metastasis and prognosis of cancer, so it is considered a potential therapeutic target. Up to now, a number of clinical trials for Claudin18.2 are underway, including solid tumors such as pancreatic cancers and gastric cancers, and the results of these trials have not yet been officially announced. This manuscript briefly describes the Claudia protein, the dual roles of Cluadin18 in cancers, and summarizes the ongoing clinical trials targeting Claudin18.2 with a view to integrating the research progress of Claudin18.2 targeted therapy. In addition, this manuscript introduces the clinical research progress of Claudin18.2 positive pancreatic cancer, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, CAR-T cell therapy, and hope to provide feasible ideas for the clinical treatment of Claudin18.2 positive pancreatic cancer.
| S-EPMC10951399 | biostudies-literature
Project description:ObjectiveEmerging evidence suggests that protease-activated receptors-1 and -2 (PAR1 and PAR2) can signal together in response to proteases found in the rapidly changing microenvironment of damaged blood vessels. However, it is unknown whether PAR1 and PAR2 promote or mitigate the hyperplastic response to arterial injury. Using cell-penetrating PAR1 pepducins and mice deficient in PAR1 or PAR2, we set out to determine the respective contributions of the receptors to hyperplasia and phenotypic modulation of smooth muscle cells (SMCs) in response to arterial injury.Methods and resultsSMCs were strongly activated by PAR1 stimulation, as evidenced by increased mitogenesis, mitochondrial activity, and calcium mobilization. The effects of chronic PAR1 stimulation following vascular injury were studied by performing carotid artery ligations in mice treated with the PAR1 agonist pepducin, P1pal-13. Histological analysis revealed that PAR1 stimulation caused striking hyperplasia, which was ablated in PAR1(-/-) and, surprisingly, PAR2(-/-) mice. P1pal-13 treatment yielded an expression pattern consistent with a dedifferentiated phenotype in carotid artery SMCs. Detection of PAR1-PAR2 complexes provided an explanation for the hyperplastic effects of the PAR1 agonist requiring the presence of both receptors.ConclusionsWe conclude that PAR2 regulates the PAR1 hyperplastic response to arterial injury leading to stenosis.
| S-EPMC3241440 | biostudies-literature
Project description:PAR-1 is expressed not only in epithelium, neurons, astrocytes, immune cells, but also in cancer-associated fibroblasts, ECs (epithelial cells), myocytes of blood vessels, mast cells, and macrophages in tumor microenvironment, whereas PAR-1 stimulates macrophages to synthesize and secrete thrombin as well as other growth factors, resulting in enhanced cell proliferation, tumor growth and metastasis. Therefore, considerable effort has been devoted to the development of inhibitors targeting PAR-1. Here, we provide a comprehensive review of PAR-1's role in cancer invasiveness and dissemination, as well as potential therapeutic strategies targeting PAR-1 signaling.
| S-EPMC5739818 | biostudies-literature
Project description:ObjectivePlatelet activation after stimulation of PAR (protease-activated receptor) 4 is heightened in platelets from blacks compared with those from whites. The difference in PAR4 signaling by race is partially explained by a single-nucleotide variant in PAR4 encoding for either an alanine or threonine at amino acid 120 in the second transmembrane domain. The current study sought to determine whether the difference in PAR4 signaling by this PAR4 variant is because of biased Gq signaling and whether the difference in PAR4 activity results in resistance to traditional antiplatelet intervention.Approach and resultsMembranes expressing human PAR4-120 variants were reconstituted with either Gq or G13 to determine the kinetics of G protein activation. The kinetics of Gq and G13 activation were both increased in membranes expressing PAR4-Thr120 compared with those expressing PAR4-Ala120. Further, inhibiting PAR4-mediated platelet activation by targeting COX (cyclooxygenase) and P2Y12 receptor was less effective in platelets from subjects expressing PAR4-Thr120 compared with PAR4-Ala120. Additionally, ex vivo thrombus formation in whole blood was evaluated at high shear to determine the relationship between PAR4 variant expression and response to antiplatelet drugs. Ex vivo thrombus formation was enhanced in blood from subjects expressing PAR4-Thr120 in the presence or absence of antiplatelet therapy.ConclusionsTogether, these data support that the signaling difference by the PAR4-120 variant results in the enhancement of both Gq and G13 activation and an increase in thrombus formation resulting in a potential resistance to traditional antiplatelet therapies targeting COX-1 and the P2Y12 receptor.
| S-EPMC6023764 | biostudies-literature
Project description:Activated platelets play a crucial role in the pathogenesis of atherothrombotic disease and its complications. Even under treatment of antiplatelet drugs, such as acetylsalicylic acid and P2Y12 antagonists, morbidity and mortality rates of thromboembolic complications remain high. Hence, the therapeutic inhibition of protease-activated receptor (PAR)-1, which is activated by thrombin, is a novel promising approach in antiplatelet therapy. Recent data suggest that PAR-1 is mainly involved in pathological thrombus formation, but not in physiological hemostasis. Therefore, PAR-1 inhibition offers the possibility to reduce atherothrombotic events without increasing bleeding risk. So far, two emerging PAR-1 antagonists have been tested in clinical trials: vorapaxar (SCH530349; Merck & Co., Whitehouse Station, NJ, USA) and atopaxar (E5555; Eisai, Tokyo, Japan). Although in TRA-CER vorapaxar showed an unfavorable profile for patients with acute coronary syndrome in addition to standard therapy, it revealed promising results for patients with prior myocardial infarction in TRA 2P-TIMI50. Depending on the status of clinical approval, vorapaxar might be an option for patients with peripheral arterial disease to reduce limb ischemia. The second PAR-I antagonist, atopaxar, tended towards reducing major cardiovascular adverse events in acute coronary syndrome patients in a phase II trial. However, although statistically not significant, bleeding events were numerically increased in atopaxar-treated patients compared with placebo. Furthermore, liver enzymes were elevated and the relative corrected QT interval was prolonged in atopaxar-treated patients. Currently, the development of atopaxar by Eisai is discontinued. The future of this novel class of antithrombotic drugs will depend on the identification of patient groups in which the risk-benefit ratio is favorable.
| S-EPMC4107434 | biostudies-literature
Project description:The G-protein coupled receptors (GPCRs) belong to a large family of diverse receptors that are well recognized as pharmacological targets. However, very few of these receptors have been pursued as oncology drug targets. The Protease-activated receptor 1 (PAR1), which is a G-protein coupled receptor, has been shown to act as an oncogene and is an emerging anti-cancer drug target. In this paper, we provide an overview of PAR1's biased signaling role in metastatic cancers of the breast, lungs, and ovaries and describe the development of PAR1 inhibitors that are currently in clinical use to treat acute coronary syndromes. PAR1 inhibitor PZ-128 is in a Phase II clinical trial and is being developed to prevent ischemic and thrombotic complication of patients undergoing cardiac catheterization. PZ-128 belongs to a new class of cell-penetrating, membrane-tethered peptides named pepducins that are based on the intracellular loops of receptors targeting the receptor G-protein interface. Application of PZ-128 as an anti-metastatic and anti-angiogenic therapeutic agent in breast, lung, and ovarian cancer is being reviewed.
| S-EPMC6121574 | biostudies-literature
Project description:Antiplatelet therapy is the most important treatment to reduce the risk of developing recurrent thrombosis, and to prevent progression to a complete occlusion of coronary arterial disease (CAD) patients after percutaneous coronary intervention Aim of study was to investigate the relationship between response to antiplatelet drugs and global mRNA gene expression in peripheral blood cells (PBC) in patients with coronary arterial disease (CAD) All patients were treated crhonically with acetylsalicylic acid (ASA) (100 mg/day) and clopidogrel (75 mg/day). Blood samples were drown before PCI to evaluate platelet reactivity by VerifyNow® ASA and P2Y12 assays and mRNA expression was measured by Affymetrix GeneChip Human Exon 1.0 ST array.
2012-09-15 | E-GEOD-32226 | biostudies-arrayexpress
Project description:Protein C is a plasma serine protease zymogen whose active form, activated protein C (APC), exerts potent anticoagulant activity. In addition to its antithrombotic role as a plasma protease, pharmacologic APC is a pleiotropic protease that activates diverse homeostatic cell signaling pathways via multiple receptors on many cells. Engineering of APC by site-directed mutagenesis provided a signaling selective APC mutant with 3 Lys residues replaced by 3 Ala residues, 3K3A-APC, that lacks >90% anticoagulant activity but retains normal cell signaling activities. This 3K3A-APC mutant exerts multiple potent neuroprotective activities, which require the G-protein-coupled receptor, protease activated receptor 1. Potent neuroprotection in murine ischemic stroke models is linked to 3K3A-APC-induced signaling that arises due to APC's cleavage in protease activated receptor 1 at a noncanonical Arg46 site. This cleavage causes biased signaling that provides a major explanation for APC's in vivo mechanism of action for neuroprotective activities. 3K3A-APC appeared to be safe in ischemic stroke patients and reduced bleeding in the brain after tissue plasminogen activator therapy in a recent phase 2 clinical trial. Hence, it merits further clinical testing for its efficacy in ischemic stroke patients. Recent studies using human fetal neural stem and progenitor cells show that 3K3A-APC promotes neurogenesis in vitro as well as in vivo in the murine middle cerebral artery occlusion stroke model. These recent advances should encourage translational research centered on signaling selective APC's for both single-agent therapies and multiagent combination therapies for ischemic stroke and other neuropathologies.
| S-EPMC6043978 | biostudies-literature