Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 5, Pages E982-E991Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1718600115
Keywords
endothelium; cytoprotection; thrombosis; inflammation; PAR1
Categories
Funding
- National Heart, Lung, and Blood Institute [HL125275, HL112809, HL135775, T32 HL007917, T32 HL116324-02]
- Wyss Institute for Biologically Inspired Engineering at Harvard University
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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 G beta gamma, activating a PI3K/Akt pathway and eliciting a genetic program that includes suppression of NF-kappa B-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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