Inhibition of the plasma SCUBE1, a novel platelet adhesive protein, protects mice against thrombosis

Meng Ying Wu, Yuh Charn Lin, Wei Ju Liao, Cheng Fen Tu, Ming Huei Chen, Steve R. Roffler, Ruey Bing Yang

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

OBJECTIVE - Signal peptide-CUB-EGF domain-containing protein 1 (SCUBE1), a secreted and surface-exposed glycoprotein on activated platelets, promotes platelet-platelet interaction and supports platelet-matrix adhesion. Its plasma level is a biomarker of platelet activation in acute thrombotic diseases. However, the exact roles of plasma SCUBE1 in vivo remain undefined. APPROACH AND RESULTS - We generated new mutant (Δ) mice lacking the soluble but retaining the membrane-bound form of SCUBE1. Plasma SCUBE1-depleted Δ/Δ mice showed normal hematologic and coagulant features and expression of major platelet receptors, but Δ/Δ platelet-rich plasma showed impaired platelet aggregation in response to ADP and collagen treatment. The addition of purified recombinant SCUBE1 protein restored the aggregation of platelets in Δ/Δ platelet-rich plasma and further enhanced platelet aggregation in +/+ platelet-rich plasma. Plasma deficiency of SCUBE1 diminished arterial thrombosis in mice and protected against lethal thromboembolism induced by collagen-epinephrine treatment. Last, antibodies directed against the epidermal growth factor-like repeats of SCUBE1, which are involved in trans-homophilic protein-protein interactions, protected mice against fatal thromboembolism without causing bleeding in vivo. CONCLUSIONS - We conclude that plasma SCUBE1 participates in platelet aggregation by bridging adjacent activated platelets in thrombosis. Blockade of soluble SCUBE1 might represent a novel antithrombotic strategy.

Original languageEnglish
Pages (from-to)1390-1398
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume34
Issue number7
DOIs
Publication statusPublished - Jul 2014

Keywords

  • antibodies neutralizing
  • blood platelets
  • mice knockout
  • platelet aggregation
  • thrombosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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