ArticleBlood2013
Novel mechanisms for activated protein C cytoprotective activities involving noncanonical activation of protease-activated receptor 3.
Article in Blood, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
What it found
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The trial behind it
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Who cites it
57 citing papers in PubMed, 93 citations in OpenAlex.
- Protein C system defects inflicted by the malaria parasite protein PfEMP1 can be overcome by a soluble EPCR variant.Thrombosis and haemostasis · 2015Trial
- Activated protein C drives β-arrestin-2- and c-Src-dependent phosphorylation of Cav1 and modulates Cav1 association with PAR1 and GRK5.The Journal of biological chemistry · 2026Article
- Human tissue kallikrein 14 induces the expression of IL-6, IL-8, and CXCL1 in skin fibroblasts through protease-activated receptor 1 signaling.The FEBS journal · 2025Article
- Activated protein C ameliorates diabetes-induced atherosclerosis by sustaining macrophage efferocytosis.Cardiovascular diabetology · 2025Article
- A Bivalent Protease-Activated Receptor-Derived Peptide Mimics Neuronal Anti-Apoptotic Activity of Activated Protein C.Bioengineering (Basel, Switzerland) · 2025Article
- Divergent modulation of activated protein C pleiotropic functions by antibodies that differ by a single amino acid.Blood advances · 2025Article
- An orthosteric/allosteric bivalent peptide agonist comprising covalently linked protease-activated receptor-derived peptides mimics in vitro and in vivo activities of activated protein C.Journal of thrombosis and haemostasis : JTH · 2024Article
- Coagulation Protease-Driven Cancer Immune Evasion: Potential Targets for Cancer Immunotherapy.Cancers · 2024Review
- Unraveling the Molecular Mechanisms of Activated Protein C (APC) in Mitigating Reperfusion Injury and Cardiac Ischemia: a Promising Avenue for Novel Therapeutic Interventions.Journal of cardiovascular translational research · 2024Review
- Endothelial Protein C Receptor and Its Impact on Rheumatic Disease.Journal of clinical medicine · 2024Review
- Neuroprotective Effects of Noncanonical PAR1 Agonists on Cultured Neurons in Excitotoxicity.International journal of molecular sciences · 2024Article
- Selective modulation of activated protein C activities by a nonactive site-targeting nanobody library.Blood advances · 2023Article
- Protease-activated receptors in health and disease.Physiological reviews · 2023Review
- Endothelial APC/PAR1 distinctly regulates cytokine-induced pro-inflammatory VCAM-1 expression.Frontiers in molecular biosciences · 2023Article
- Diversification of PAR signaling through receptor crosstalk.Cellular & molecular biology letters · 2022Review
- Effects of intermittent hypoxia with thrombin in an in vitro model of human brain endothelial cells and their impact on PAR-1/PAR-3 cleavage.Scientific reports · 2022Article
- Article
- Protection of ischemic white matter and oligodendrocytes in mice by 3K3A-activated protein C.The Journal of experimental medicine · 2022Article
- aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete, β-arrestin-2-mediated SphK1-S1PR1-Akt signaling axis.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The direct cytoprotective activities of activated protein C (APC) on cells convey therapeutic, relevant, beneficial effects in injury and disease models in vivo and require the endothelial protein C receptor (EPCR) and protease activated receptor 1 (PAR1). Thrombin also activates PAR1, but its effects on cells contrast APC's cytoprotective effects. To gain insights into mechanisms for these contrasting cellular effects, protease activated receptor 3 (PAR3) activation by APC and thrombin was studied. APC cleaved PAR3 on transfected and endothelial cells in the presence of EPCR. Remarkably, APC cleaved a synthetic PAR3 N-terminal peptide at Arg41, whereas thrombin cleaved at Lys38. On cells, APC failed to cleave R41Q-PAR3, whereas K38Q-PAR3 was still cleaved by APC but not by thrombin. PAR3 tethered-ligand peptides beginning at amino acid 42, but not those beginning at amino acid 39, conveyed endothelial barrier-protective effects. In vivo, the APC-derived PAR3 tethered-ligand peptide, but not the thrombin-derived PAR3 peptide, blunted vascular endothelial growth factor (VEGF)-induced vascular permeability. These data indicate that PAR3 cleavage by APC at Arg41 can initiate distinctive APC-like cytoprotective effects. These novel insights help explain the differentiation of APC's cytoprotective versus thrombin's proinflammatory effects on cells and suggest a unique contributory role for PAR3 in the complex mechanisms underlying APC cytoprotective effects.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.