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

Georgina G J Hazell1, Alasdair M G Peachey1, Jack E Teasdale1

  • 1School of Clinical Sciences, University of Bristol, Bristol Royal Infirmary, Bristol, BS2 8HW, UK.

Scientific Reports
|December 21, 2016
PubMed

Insights

High endothelial shear stress normally protects against atherosclerosis via peptidase inhibitor 16 (PI16). However, inflammation reduces PI16, potentially reversing this protective effect and increasing protease activity.

Area of Science:

  • Cardiovascular Biology
  • Molecular Biology
  • Endothelial Cell Function

Background:

  • Endothelial shear stress plays a protective role against atherosclerosis.
  • This protective effect may be compromised at sites of inflammation.
  • Peptidase inhibitor 16 (PI16) is a novel shear stress-regulated gene in endothelial cells.

Purpose of the Study:

  • To investigate the role of PI16 in endothelial cells under varying shear stress conditions.
  • To determine the impact of inflammatory mediators on PI16 expression.
  • To elucidate the mechanism by which PI16 affects endothelial cell function and protease activity.

Main Methods:

  • Analysis of PI16 splice variants in human coronary artery endothelial cells (HCAECs) under shear stress.
  • Assessment of PI16 expression changes induced by tumor necrosis factor-alpha (TNFα) and interleukin-1 beta (IL-1β).
  • Immunohistochemical localization of PI16 in human coronary artery tissues.
  • Overexpression of PI16 in HCAECs using adenovirus to study its effects on migration and matrix metalloproteinase (MMP) activity.
  • Biochemical assays to determine PI16's interaction with MMP2.

Main Results:

  • Four PI16 mRNA splice variants were identified as highly regulated by shear stress in HCAECs.
  • Inflammatory mediators TNFα and IL-1β significantly reduced PI16 expression.
  • PI16 was detected in human coronary endothelium, neointima, and medial smooth muscle cells.
  • PI16 overexpression inhibited HCAEC migration and secreted MMP activity.
  • PI16 was found to inhibit MMP2 by binding to a loop near its active site.

Conclusions:

  • PI16 contributes to the inhibition of protease activity under high endothelial shear stress.
  • Inflammation can reverse the protective effects of PI16 by reducing its expression.
  • These findings suggest a mechanism by which inflammation may promote atherosclerosis by counteracting shear stress-induced protection.

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