Study Data from St. Louis University Provide New Insights into Heparin Therapy (Engineering D-helix of antithrombin in alpha-1-proteinase inhibitor confers antiinflammatory properties on the chimeric serpin)
By a News Reporter-Staff News Editor at Biotech Week -- Data detailed on Drugs and Therapies have been presented. According to news originating from St. Louis, Missouri, by NewsRx correspondents, research stated, "Antithrombin (AT) is a heparin-binding serpin in plasma which regulates the proteolytic activity of procoagulant proteases of the clotting cascade. In addition to being an anticoagulant, AT also exhibits antiinflammatory activities when it binds to cell surface heparan sulfate proteoglycans (HSPGs) on the endothelium via its basic residues of D-helix to elicit intracellular signalling responses."
Our news journalists obtained a quote from the research from St. Louis University, "By contrast to AT, alpha(1)-proteinase inhibitor (alpha(1)-PI) is a non-heparin-binding serpin that exhibits very slow reactivity with coagulation proteases and possesses no HSPG-dependent antiinflammatory properties. To determine whether the antiinflammatory signaling specificity of AT can be transferred to alpha(1)-PI, we replaced the D-helix of human alpha(1)-PI with the corresponding sequence of human AT and expressed the chimeric serpin alpha(1)-PI/D-helix) in a bacterial expression system. High molecular weight heparin bound to alpha(1)-PhD-helix and accelerated the inhibition of thrombin by the serpin mutant by a template mechanism reminiscent of the cofactor effect of heparin on inhibition of thrombin by AT. Like AT, alpha(1)-PI/D-helix exhibited antiinflammatory properties in both cellular and animal models. Thus, alpha(1)-PI/D-helix inhibited the barrier-disruptive effect of proinflammatory cytokines and inhibited the activation of nuclear factor-kappa B transcription factor in lipopolysaccharide-stimulated endothelial cells by a concentration-dependent manner. Furthermore, the chimeric serpin reduced lipopolysaccharide-mediated lethality, elicited a vascular protective effect and inhibited infiltration of activated leukocytes to the peritoneal cavity of mice in an HMGB1-mediated inflammatory model."
According to the news editors, the research concluded: "These results suggest that grafting the D-helix of AT to alpha(1)-PI confers antiinflammatory properties on the serpin and that the chimeric serpin may have therapeutic utility for treating inflammatory disorders."
For more information on this research see: Engineering D-helix of antithrombin in alpha-1-proteinase inhibitor confers antiinflammatory properties on the chimeric serpin. Thrombosis and Haemostasis, 2014;112(1):164-175. Thrombosis and Haemostasis can be contacted at: Schattauer Gmbh-Verlag Medizin Naturwissenschaften, Holderlinstrasse 3, D-70174 Stuttgart, Germany (see also Drugs and Therapies).
The news correspondents report that additional information may be obtained from L.K. Yang, St. Louis University, Sch Med, Edward A Doisy Dept. of Biochem & Mol Biol, St Louis, MO 63104, United States. Additional authors for this research include P. Dinarvand, S.H. Qureshi and A.R. Rezaie.
Keywords for this news article include: Antithrombins, Heparin, Serpins, Missouri, Protease, St. Louis, Angiology, Engineering, United States, Enzyme Therapy, Respiratory Agents, Drugs and Therapies, Enzymes and Coenzymes, North and Central America, Alpha 1-proteinase Inhibitor, Alpha-1-proteinase inhibitor
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