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Titolo:
A TISSUE-PLASMINOGEN ACTIVATOR P-SELECTIN FUSION PROTEIN IS AN EFFECTIVE THROMBOLYTIC AGENT/
Autore:
FUJISE K; REVELLE BM; STACY L; MADISON EL; YEH ETH; WILLERSON JT; BECK PJ;
Indirizzi:
UNIV TEXAS,HLTH SCI CTR,CARDIOVASC RES CTR,INST MOL MED PREVENT HUMANDIS,STE 4200,6431 FANNIN HOUSTON TX 77030 UNIV TEXAS,HLTH SCI CTR,DIV MOL MED,DEPT INTERNAL MED HOUSTON TX 77030 UNIV TEXAS,HLTH SCI CTR,DIV CARDIOL,DEPT INTERNAL MED HOUSTON TX 77030 TEXAS HEART INST HOUSTON TX 77025 TEXAS BIOTECHNOL CORP HOUSTON TX 00000 SCRIPPS CLIN & RES INST,DEPT VASC BIOL LA JOLLA CA 00000
Titolo Testata:
Circulation
fascicolo: 3, volume: 95, anno: 1997,
pagine: 715 - 722
SICI:
0009-7322(1997)95:3<715:ATAPFP>2.0.ZU;2-X
Fonte:
ISI
Lingua:
ENG
Soggetto:
GRANULE MEMBRANE-PROTEIN; SINGLE-CHAIN UROKINASE; SUPEROXIDE ANION RELEASE; CANINE CORONARY-ARTERIES; RAT MESENTERIC-ARTERIES; HUMAN-ENDOTHELIAL-CELLS; WEIBEL-PALADE BODIES; P-SELECTIN; MONOCLONAL-ANTIBODY; REPERFUSION INJURY;
Keywords:
PLASMINOGEN ACTIVATORS; THROMBOLYSIS; P-SELECTIN; CYCLIC FLOW VARIATIONS; ACUTE CORONARY SYNDROMES;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
57
Recensione:
Indirizzi per estratti:
Citazione:
K. Fujise et al., "A TISSUE-PLASMINOGEN ACTIVATOR P-SELECTIN FUSION PROTEIN IS AN EFFECTIVE THROMBOLYTIC AGENT/", Circulation, 95(3), 1997, pp. 715-722

Abstract

Background P-selectin is expressed on the surface of activated endothelial cells and platelets. We hypothesized that a tissue plasminogen activator (TPA)/P-selectin fusion protein would have not only thrombolytic activity but also might target TPA to the thrombi. In addition, itseemed possible that this chimeric protein would competitively inhibit the binding of native P-selectin on endothelial cells and platelets to leukocytes and thus further promote thrombolysis. Methods and Results The full-length, plasminogen activator inhibitor-1-resistant form of TPA (TPA(IR)) together with two TPA(IR)/P-selectin fusion constructs(P280(IR) and P121(IR)) were expressed with the use of baculovirus vectors. After infection of Sf-21 cells with the recombinant baculovirus, recombinant TPA(IR) and P-selectin/TPA(IR) fusion proteins were purified with the use of metal ion chromatography. The intact protease activity of TPA(IR), and the ligand binding capability of P-selectin wereconfirmed through indirect chromogenic and cell binding assays, respectively. These molecules were assessed both in vitro and in vivo for thrombolytic activity. In vitro clot lysis assays indicated equal efficacy of TPA(IR), P280(IR), and P121(IR) (P>.5). The in vive efficacy was tested in a cyclic flow variation model with the use of the rat mesenteric artery. Compared with saline control treatment, reduction in cyclic flow variations was significant (P<.05) and similar (P>.5) among TPA(IR), P280(IR), and P121(IR). No significant bleeding was noted among treated animals. Conclusions Chimeric proteins P280(IR), and P121(IR) have clot lysis activities that are similar to TPA(IR) both in vitro and in vivo. These chimeric proteins also bind to P-selectin ligand in vitro. Thus, these proteins may provide an efficient method of targeting TPA to the thrombotic region. Further experimental analysis withthe use of larger animal coronary occlusion models should help determine the future value of these proteins as clinical therapeutic agents.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 09/04/20 alle ore 10:22:54