PI16 is a shear stress and inflammation-regulated inhibitor of MMP2
Open accessAbstract
Raised endothelial shear stress is protective against atherosclerosis but such protection may be lost at sites of inflammation. We found that four splice variants of the peptidase inhibitor 16 (PI16) mRNA are among the most highly shear stress regulated transcripts in human coronary artery endothelial cells (HCAECs), in vitro but that expression is reduced by inflammatory mediators TNFα and IL-1β. Immunohistochemistry demonstrated that PI16 is expressed in human coronary endothelium and in a subset of neointimal cells and medial smooth muscle cells. Adenovirus-mediated PI16 overexpression inhibits HCAEC migration and secreted matrix metalloproteinase (MMP) activity. Moreover, PI16 inhibits MMP2 in part by binding an exposed peptide loop above the active site. Our results imply that, at high endothelial shear stress, PI16 contributes to inhibition of protease activity; protection that can be reversed during inflammation.
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PI16 and ADAMDEC1, whose expression is strongly suppressed by inflammatory response, were increased in 3TC-treated spheroids.
“Both PI16 and ADAMDEC1, whose expression is strongly suppressed by inflammatory response (91, 92), were increased in 3TC-treated spheroids (Fig. 7F).”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [91]
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- Authors
- Hazell, G. G. J., Peachey, A. M. G., Teasdale, J. E., Sala-Newby, G. B., Angelini, G. D., Newby, A. C., & White, S. J.
- Affiliations
- Bristol Royal Infirmary (GB)
- Manchester Metropolitan University (GB)
- Corresponding author
- White, Stephen J.
- Venue
- Scientific Reports
- Published
- 2016-12-20
- Volume
- 6
- Issue
- 1
- Pages
- 39553-39553
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5171773
- OpenAlex
- W2567034678
- Cited by
- 83
- References
- 54
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 12 · 2023: 15 · 2022: 2 · 2021: 10 · 2020: 15 · 2019: 6 · 2018: 6 · 2017: 1
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- e-space (Manchester Metropolitan University) (acceptedVersion)
- Explore Bristol Research (acceptedVersion, cc-by)
- Bristol Research (University of Bristol) (submittedVersion, cc-by)
- Funders
- British Heart Foundation (CH95001, RG/09/006/27918, FS/12/77/29887, PG/11/44/28972)
- University of Bristol
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- PI16, MMP-2, endothelial shear stress, inflammation, atherosclerosis, coronary artery endothelial cells, splice variants, TNF-α, IL-1β, neointima, smooth muscle cells, endothelial cell migration, protease inhibition, adenoviral overexpression
- MeSH terms
- Carrier Proteins, Cell Movement, Coronary Vessels, Endothelium, Vascular, Gene Expression Regulation, Glycoproteins, Humans, Immunohistochemistry, Inflammation, Peptides, Phenotype, Stress, Mechanical, Tumor Necrosis Factor-alpha, Alternative Splicing, Peptide Library, Matrix Metalloproteinase 2, Endothelial Cells
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