These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: Shear stress is a positive regulator of thimet oligopeptidase (EC3.4.24.15) in vascular endothelial cells: consequences for MHC1 levels.
    Author: Guinan AF, Rochfort KD, Fitzpatrick PA, Walsh TG, Pierotti AR, Phelan S, Murphy RP, Cummins PM.
    Journal: Cardiovasc Res; 2013 Aug 01; 99(3):545-54. PubMed ID: 23708739.
    Abstract:
    AIMS: Thimet oligopeptidase (TOP, endopeptidase EC3.4.24.15) is a soluble metallopeptidase known to be expressed within the mammalian vasculature. We examine for the first time the relationship between TOP expression and laminar shear stress, a haemodynamic force associated with endothelium-mediated vascular homeostasis. METHODS AND RESULTS: Human and bovine aortic endothelial cells were exposed to physiological levels of laminar shear (0-10 dynes/cm², 24-48 h) and monitored for TOP expression using promoter activity assay, qRT-PCR, western blotting, and immunocytochemistry. Using a luciferase reporter encoding the full-length rat TOP promoter, initial studies demonstrated shear-dependent promoter activation (~five-fold). TOP mRNA and protein were also consistently up-regulated by shear, events which could be completely prevented by pre-treatment of cells with either N-acetylcysteine, superoxide dismutase, or catalase, confirming ROS involvement. Consistent with this, targeted inhibition of NADPH oxidase (apocynin, NSC23766, NOX4 siRNA) had a similar blocking effect. Finally, in view of its pivotal role in cellular antigen presentation and major histocompatibility complex (MHC) class-1 regulation, we hypothesized that the shear-dependent induction of TOP may lower MHC1 expression. In this respect, we observed that recombinant TOP over-expression in static HAECs dose-dependently depleted MHC1 (>60%), while siRNA-mediated blockade of TOP induction in sheared HAECs led to substantially elevated MHC1 (~66%). CONCLUSION: Our findings demonstrate that laminar shear positively regulates endothelial TOP expression. Moreover, a role for ROS production by NADPH oxidase is indicated. Finally, our studies suggest that shear-dependent TOP induction down-regulates MHC1 levels, pointing to a role for TOP in the flow-mediated regulation of endothelial immunogenicity.
    [Abstract] [Full Text] [Related] [New Search]