TAILIEUCHUNG - Báo cáo khoa học: High negative charge-to-size ratio in polyphosphates and heparin regulates factor VII-activating protease

Factor VII-activating protease (FSAP) circulates as an inactive zymogen in the plasma. FSAP also regulates fibrinolysis by activating pro-urokinase or cellular activation via cleavage of platelet-derived growth factor BB (PDGF-BB). As the Marburg I polymorphism of FSAP, with reduced enzymatic activity, is a risk factor for atherosclerosis and liver fibrosis, the regulation of FSAP activity is of major importance. | High negative charge-to-size ratio in polyphosphates and heparin regulates factor VII-activating protease 1 12 3 Lars Muhl Sebastian P. Galuska Katariina Oorni Laura Hernandez-Ruiz Luminita-Cornelia A n H roi -Co I mn r4 p 11H fy If CmtiKfa r1 1 1 a I IQ T Proi cc n o r1 Fo 11V Ù Rill 3 Po rĩ T I H anon2 Hieiueimei uo eyei aus . leissnei ex . uiz eu . ovanen and Sandip M. Kanse1 1 Institute for Biochemistry Justus-Liebig-University Giessen Germany 2 Wihuri Research Institute Helsinki Finland 3 Unidad de Investigacion HospitalUniversidad Puerta delMar and Universidad de Cadiz Spain 4 Philipps University Marburg Germany Keywords FSAP heparin mast cells platelets polyphosphate Correspondence S. M. Kanse Institute for Biochemistry Justus-Liebig-University Giessen Friedrichstrasse 24 35392 Giessen Germany Fax 49 641 9947509 Tel 49 641 9947521 E-mail . Received 12 March 2009 revised 28 May 2009 accepted 29 June 2009 doi Factor VlI-activating protease FSAP circulates as an inactive zymogen in the plasma. FSAP also regulates fibrinolysis by activating pro-urokinase or cellular activation via cleavage of platelet-derived growth factor BB PDGF-BB . As the Marburg I polymorphism of FSAP with reduced enzymatic activity is a risk factor for atherosclerosis and liver fibrosis the regulation of FSAP activity is of major importance. FSAP is activated by an auto-catalytic mechanism which is amplified by heparin. To further investigate the structural requirements of polyanions for controlling FSAP activity we performed binding activation and inhibition studies using heparin and derivatives with altered size and charge as well as other glycosaminoglycans. Heparin was effective in binding to and activating FSAP in a size- and charge density-dependent manner. Polyphosphate was more potent than heparin with regard to its interactions with FSAP. Heparin was also an effective co-factor for inhibition of FSAP by .

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• Factor VII activating protease (FSAP) circulates as an inactive zymogen in the plasma
• FSAP also regulates fibrinolysis by activating pro urokinase or cellular activation via cleavage of platelet derived growth factor BB (PDGF BB)
• As the Marburg I polymorphism of FSAP
• with reduced enzymatic activity
• is a risk factor for atherosclerosis and liver fibrosis
• the regulation of FSAP activity is of major importance
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