Cited by 83Protease and Inhibitor MechanismsBlood Coagulation and Thrombosis MechanismsNitric Oxide and Endothelin Effects

PI16 is a shear stress and inflammation-regulated inhibitor of MMP2

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Hazell, Georgina G. J., Peachey, Alasdair M. G., Teasdale, Jack E., Sala-Newby, Graciela B., Angelini, Gianni D., Newby, Andrew C., White, Stephen J.·2016·Scientific Reports

Abstract

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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  1. Ilegbusi O. & Valaski-Tuema E. In Biomedical Simulation, Proceedings Vol. 5958 Lecture Notes in Computer Science (eds Bello F. & Cotin S.) 98– 107 (Springer-Verlag: Berlin, 2010).
  2. White S. J., Newby A. C. & Johnson T. W. Endothelial erosion of plaques as a substrate for coronary thrombosis. Thromb. Haemost. 115, 509– 519, doi: 10.1160/TH15-09-0765 (2016). 26791872 · DOI

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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)
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
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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