Faculty Collaboration Database

PAR1 agonists stimulate APC-like endothelial cytoprotection and confer resistance to thromboinflammatory injury. Proc Natl Acad Sci U S A 2018 Jan 30;115(5):E982-E991

Date

01/19/2018

Pubmed ID

29343648

Pubmed Central ID

PMC5798377

DOI

10.1073/pnas.1718600115

Scopus ID

2-s2.0-85041197789 (requires institutional sign-in at Scopus site)   53 Citations

Abstract

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.

Author List

De Ceunynck K, Peters CG, Jain A, Higgins SJ, Aisiku O, Fitch-Tewfik JL, Chaudhry SA, Dockendorff C, Parikh SM, Ingber DE, Flaumenhaft R

Author

Christopher Dockendorff PhD Assistant Professor, Organic and Medicinal Chemistry in the Chemistry department at Marquette University

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Endothelial Cells
Factor Xa
Gene Knockdown Techniques
Glycoproteins
Human Umbilical Vein Endothelial Cells
Humans
Inflammation
Lipopolysaccharides
Male
Mice
Mice, Inbred C57BL
Microcirculation
Peptide Hydrolases
Receptor, PAR-1
Receptors, G-Protein-Coupled
Signal Transduction
Thrombosis
Transcription, Genetic
Up-Regulation