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Proteinase-activated receptor 1 activation induces epithelial apoptosis and increases intestinal permeability
Open accessAbstract
Proteinase-activated receptor 1 (PAR 1 )-mediated inflammation remains poorly understood. Here we characterize previously unrecognized effects of PAR 1 -induced apoptosis signaling, which contributes to epithelial barrier dysfunction. Incubation of epithelial cells with PAR 1 agonists induced apoptosis and increased epithelial permeability in a caspase-3-dependent manner. Similarly, studies in vivo demonstrated that intracolonic infusion with PAR 1 agonists increased colonic permeability in mice, and that this effect was abolished by pretreatment with a caspase-3 inhibitor. PAR 1 agonists induced tight junctional zonula-occludens 1 disruption and apoptotic nuclear condensation. Investigation into signaling pathways showed that these effects were dependent on caspase-3, tyrosine kinase, and myosin light chain kinase. Conversely, the Src kinase inhibitor PP1 augmented zonula-occludens 1 injury and nuclear condensation induced by PAR 1 agonists. These results support a role for proteinases and PARs in intestinal disease and provide new directions for possible therapeutic applications of PAR 1 antagonists.
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“PARs have been implicated in the pathogenesis of colorectal cancer138 and inflammatory and functional intestinal disorders.139–141”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [140]
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Self-citation
Metadata
- Authors
- Chin, A. C., Vergnolle, N., MacNaughton, W. K., Wallace, J. L., Hollenberg, M. D., & Buret, A. G.
- Affiliations
- University of Calgary (CA)
- Mucosal Inflammation Research Group and Departments of Biological Sciences,Pharmacology and Therapeutics, and Physiology and Biophysics, University of Calgary, Calgary, AB, Canada T2N 1N4
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-09-05
- Volume
- 100
- Issue
- 19
- Pages
- 11104-11109
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC196934
- OpenAlex
- W1981419554
- Cited by
- 149
- References
- 57
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 7 · 2023: 4 · 2022: 9 · 2021: 4 · 2020: 3 · 2019: 11 · 2018: 2 · 2017: 6 · 2016: 3 · 2015: 4 · 2014: 5 · 2013: 8 · 2012: 6
- FWCI
- 4.98
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Crohn's and Colitis Foundation
- Crohn's and Colitis Foundation of Canada
- Canadian Association of Gastroenterology
- Fondation pour la Recherche Médicale
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- protease-activated receptor 1, epithelial apoptosis, intestinal permeability, epithelial barrier dysfunction, caspase-3, zonula occludens-1, tight junctions, myosin light chain kinase, tyrosine kinase, Src kinase, protein phosphatase 1, colonic permeability, PAR1 antagonists, intestinal inflammation
- MeSH terms
- Animals, Humans, Intestinal Absorption, Male, Membrane Proteins, Mice, Inbred C57BL, Myosin-Light-Chain Kinase, Permeability, Phosphoproteins, Protein-Tyrosine Kinases, Apoptosis, Receptors, Thrombin, Caspase 1, Receptor, PAR-1, Mice, Zonula Occludens-1 Protein
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