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 cancer and inflammatory and functional intestinal disorders.
“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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- 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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