Expression of hirudin fusion proteins in mammalian cells : A strategy for prevention of intravascular thrombosis

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Riesbeck, KristianLund University,Lunds universitet,Klinisk mikrobiologi, Malmö,Forskargrupper vid Lunds universitet,Clinical Microbiology, Malmö,Lund University Research Groups,Skåne University Hospital,Hammersmith Hospital (author)

Expression of hirudin fusion proteins in mammalian cells : A strategy for prevention of intravascular thrombosis

Article/chapterEnglish1998

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1998

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LIBRIS-ID:oai:lup.lub.lu.se:a372514d-4cc9-4aac-a341-a37142b1596f
https://lup.lub.lu.se/record/a372514d-4cc9-4aac-a341-a37142b1596fURI
https://doi.org/10.1161/01.CIR.98.24.2744DOI

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Language:English
Summary in:English

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Background - Intravascular thrombosis occurs in disorders of diverse pathogeneses, including allograft and xenograft rejection. In this in vitro study, we describe an approach for tethering the specific thrombin inhibitor hirudin to plasma membranes as part of a genetic strategy for regulating intravascular coagulation. Methods and Results - An HLA class I leader sequence was fused with hirudin linked to domains 3 and 4 of human CD4 and intracytoplasmic sequence from either CD4 or human P-selectin. The constructs were transfected into mouse fibroblasts, Chinese hamster ovary (CHO)-K1 cells, immortalized porcine endothelial cells (IPECs), and a pituitary secretory cell line (D16/16). Thrombin binding to the hirudin fusion proteins expressed on fibroblasts and CHO-K1 cells could be blocked by an anti- hirudin monoclonal antibody and by pretreatment of thrombin with either the synthetic tripeptide thrombin inhibitor PPACK or native hirudin. Hirudin expression significantly modified the procoagulant phenotype of IPECs in human plasma, leading to prolongation of clotting times. Hirudin-CD4-P- selectin fusion proteins accumulated in adrenocorticotropic hormone- containing granules in D16/16 cells, with no cell surface expression except on activation with phorbol ester, when hirudin relocated to the outer membrane. Conclusions - Hirudin fusion proteins were expressed on mammalian cells, where they reduced local thrombin levels and inhibited fibrin formation. Regulated expression was achieved on activated cells by use of the cytoplasmic sequence from P-selectin. In vivo, these fusion proteins may prove useful transgenic or gene therapy agents for preventing intravascular thrombosis.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Kardiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Cardiac and Cardiovascular Systems hsv//eng
Anticoagulants
Coagulation
Thrombosis
Transplantation

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Chen, DaxinHammersmith Hospital (author)
Kemball-Cook, GeoffreyHammersmith Hospital (author)
McVey, John H.Hammersmith Hospital (author)
George, Andrew J.T.Hammersmith Hospital (author)
Tuddenham, Edward G.D.Hammersmith Hospital (author)
Dorling, AnthonyHammersmith Hospital (author)
Lechler, Robert I.Hammersmith Hospital (author)
Klinisk mikrobiologi, MalmöForskargrupper vid Lunds universitet (creator_code:org_t)

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In:Circulation98:24, s. 2744-27520009-7322

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cardiac and Card ...

Articles in the publication: Circulation

By the university: Lund University

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