PAR1 agonists stimulate APC-like endothelial cytoprotection and confer resistance to thromboinflammatory injury

Stimulation of protease-activated receptor 1 (PAR1) on endothelium by activated protein C (APC) is protective in several animal models of disease, and APC has been used clinically in severe sepsis and wound healing. Clinical use of APC, however, is limited by its immunogenicity and its anticoagulant...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 115; no. 5; pp. E982 - E991
Main Authors De Ceunynck, Karen, Peters, Christian G., Jain, Abhishek, Higgins, Sarah J., Aisiku, Omozuanvbo, Fitch-Tewfik, Jennifer L., Chaudhry, Sharjeel A., Dockendorff, Chris, Parikh, Samir M., Ingber, Donald E., Flaumenhaft, Robert
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 30.01.2018
SeriesPNAS Plus
Subjects
1-Phosphatidylinositol 3-kinase
Activated protein C
AKT protein
Animal models
Biological Sciences
Blood vessels
Endothelium
Genetics
Immunogenicity
Inflammation
Medical treatment
Molecules
NF-κB protein
PNAS Plus
Proteinase-activated receptor 1
Proteins
Sepsis
Signal transduction
Signaling
Thrombin
Thrombosis
Transcription activation
Transcription factors
Wound healing
endothelium
thrombosis
cytoprotection
PAR1
inflammation
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Summary:Stimulation of protease-activated receptor 1 (PAR1) on endothelium by activated protein C (APC) is protective in several animal models of disease, and APC has been used clinically in severe sepsis and wound healing. Clinical use of APC, however, is limited by its immunogenicity and its anticoagulant activity. We show that a class of small molecules termed “parmodulins” that act at the cytosolic face of PAR1 stimulates APC-like cytoprotective signaling in endothelium. Parmodulins block thrombin generation in response to inflammatory mediators and inhibit platelet accumulation on endothelium cultured under flow. Evaluation of the antithrombotic mechanism showed that parmodulins induce cytoprotective signaling through Gβγ, activating a PI3K/Akt pathway and eliciting a genetic program that includes suppression of NF-κB–mediated transcriptional activation and up-regulation of select cytoprotective transcripts. STC1 is among the up-regulated transcripts, and knockdown of stanniocalin-1 blocks the protective effects of both parmodulins and APC. Induction of this signaling pathway in vivo protects against thromboinflammatory injury in blood vessels. Small-molecule activation of endothelial cytoprotection through PAR1 represents an approach for treatment of thromboinflammatory disease and provides proof-of-principle for the strategy of targeting the cytoplasmic surface of GPCRs to achieve pathway selective signaling.
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1K.D.C. and C.G.P. contributed equally to this work.
2Present address: Department of Biomedical Engineering, Dwight Look College of Engineering, Texas A&M University, College Station, TX 77843.
Author contributions: K.D.C., C.G.P., A.J., S.J.H., O.A., J.L.F.-T., D.E.I., and R.F. designed research; K.D.C., C.G.P., A.J., S.J.H., O.A., J.L.F.-T., and S.A.C. performed research; C.D. contributed new reagents/analytic tools; K.D.C., C.G.P., A.J., S.A.C., C.D., S.M.P., D.E.I., and R.F. analyzed data; and K.D.C., C.G.P., A.J., S.M.P., D.E.I., and R.F. wrote the paper.
Edited by Barry S. Coller, The Rockefeller University, New York, NY, and approved December 18, 2017 (received for review November 1, 2017)
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1718600115