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

被引:54
作者
De Ceunynck, Karen [1 ]
Peters, Christian G. [1 ]
Jain, Abhishek [2 ,10 ]
Higgins, Sarah J. [3 ,4 ]
Aisiku, Omozuanvbo [1 ]
Fitch-Tewfik, Jennifer L. [1 ]
Chaudhry, Sharjeel A. [1 ]
Dockendorff, Chris [5 ]
Parikh, Samir M. [3 ,4 ]
Ingber, Donald E. [2 ,6 ,7 ,8 ,9 ]
Flaumenhaft, Robert [1 ]
机构
[1] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Hemostasis & Thrombosis, Boston, MA 02115 USA
[2] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA
[3] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Nephrol, Boston, MA 02115 USA
[4] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Ctr Vasc Biol Res, Boston, MA 02115 USA
[5] Marquette Univ, Dept Chem, Milwaukee, WI 53201 USA
[6] Boston Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA
[7] Harvard Med Sch, Boston, MA 02115 USA
[8] Boston Childrens Hosp, Dept Surg, Boston, MA 02115 USA
[9] Harvard Univ, Harvard John A Paulson Sch Engn & Appl Sci, Cambridge, MA 02138 USA
[10] Texas A&M Univ, Dwight Look Coll Engn, Dept Biomed Engn, College Stn, TX 77843 USA
关键词
endothelium; cytoprotection; thrombosis; inflammation; PAR1; ACTIVATED PROTEIN-C; G-BETA-GAMMA; REDUCED ANTICOAGULANT ACTIVITY; GENE-EXPRESSION; FACTOR-XA; PROCOAGULANT ACTIVITY; PLATELET ACTIVATION; THROMBUS FORMATION; DEPENDENT PATHWAY; RECEPTOR;
D O I
10.1073/pnas.1718600115
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:E982 / E991
页数:10
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