The disulfide isomerase ERp72 supports arterial thrombosis in mice

Junsong Zhou, Yi Wu, Fengwu Chen, Lu Wang, Lubica Rauova, Vincent M. Hayes, Mortimer Poncz, Hong Li, Tong Liu, Junling Liu, David W. Essex

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Several CGHC motif–containing disulfide isomerases support thrombosis. We here report that endoplasmic reticulum protein 72 (ERp72), with 3 CGHC redox-active sites (ao, a, and a9), supports thrombosis. We generated a new conditional knockout mouse model and found that Tie2-Cre/ERp72fl/fl mice with blood and endothelial cells lacking ERp72 had prolonged tail bleeding times and decreased platelet accumulation in laser-induced cremaster arteriole injury and FeCl3-induced mesenteric arterial injury. Fibrin deposition was decreased in the laser injury model. Both platelet and fibrin accumulation defects were fully rescued by infusion of recombinant ERp72 containing functional a and a9 CGHC motifs (ERp72(oo-ss-ss)). Infusion of ERp72 containing inactivated a and a9 CGHC motifs (ERp72(ss-oo-oo)) inhibited platelet accumulation and fibrin deposition in wild-type mice. Infusion of ERp72(oo-ss-ss) into b3-null mice increased fibrin deposition in the absence of platelets. ERp72-null platelets had defective aggregation, JON/A binding, P-selectin expression, and adenosine triphosphate (ATP) secretion. The aggregation and ATP secretion defects were fully rescued by ERp72(oo-ss-ss) but partially rescued by ERp72(ss-oo-ss) and ERp72(ss-ss-oo). Aggregation and ATP secretion of human platelets was potentiated by ERp72(oo-ss-ss) but inhibited by ERp72(ss-oo-ss) and ERp72(ss-ss-oo). These data suggest that both the a and a9 active sites are required for platelet function. ERp72 bound poorly to b3-null mouse platelets, and the addition of ERp72(oo-ss-ss) to human platelets generated thiols in aIIbb3, suggesting a direct interaction of ERp72 with aIIbb3. Defective aggregation of ERp72-null platelets was recovered by ERp72, but not other thiol isomerases. In summary, ERp72 plays a critical role in platelet function and coagulation through the a and a9 CGHC motifs.

Original languageEnglish (US)
Pages (from-to)817-828
Number of pages12
JournalBlood
Volume130
Issue number6
DOIs
StatePublished - Aug 10 2017

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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