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The disulfide isomerase ERp72 supports arterial thrombosis in mice.
Zhou, Junsong; Wu, Yi; Chen, Fengwu; Wang, Lu; Rauova, Lubica; Hayes, Vincent M; Poncz, Mortimer; Li, Hong; Liu, Tong; Liu, Junling; Essex, David W.
Afiliação
  • Zhou J; The Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
  • Wu Y; Sol Sherry Thrombosis Research Center, Division of Hematology, Department of Medicine, Temple University School of Medicine, Philadelphia, PA.
  • Chen F; The Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
  • Wang L; Sol Sherry Thrombosis Research Center, Division of Hematology, Department of Medicine, Temple University School of Medicine, Philadelphia, PA.
  • Rauova L; The Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
  • Hayes VM; Sol Sherry Thrombosis Research Center, Division of Hematology, Department of Medicine, Temple University School of Medicine, Philadelphia, PA.
  • Poncz M; Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA.
  • Li H; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
  • Liu T; Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA.
  • Liu J; Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA.
  • Essex DW; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Blood ; 130(6): 817-828, 2017 08 10.
Article em En | MEDLINE | ID: mdl-28576878
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 a'), 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 a' CGHC motifs (ERp72(oo-ss-ss)). Infusion of ERp72 containing inactivated a and a' CGHC motifs (ERp72(ss-oo-oo)) inhibited platelet accumulation and fibrin deposition in wild-type mice. Infusion of ERp72(oo-ss-ss) into ß3-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 a' active sites are required for platelet function. ERp72 bound poorly to ß3-null mouse platelets, and the addition of ERp72(oo-ss-ss) to human platelets generated thiols in αIIbß3, suggesting a direct interaction of ERp72 with αIIbß3. 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 a' CGHC motifs.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Trombose / Plaquetas / Glicoproteínas de Membrana Limite: Animals / Humans Idioma: En Revista: Blood Ano de publicação: 2017 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Trombose / Plaquetas / Glicoproteínas de Membrana Limite: Animals / Humans Idioma: En Revista: Blood Ano de publicação: 2017 Tipo de documento: Article País de afiliação: China