Maria McGee1, William D Wagner. 1. Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. mmcgee@wfubmc.edu
Abstract
OBJECTIVE: Changes in chondroitin sulfate (CS) proteoglycan (PG) during atherosclerosis are associated with chronic inflammatory changes and increased incidence of thrombosis. To explore how glycosaminoglycan changes could influence the thrombogenicity of atherosclerotic lesions, water-transfer reactions were examined during activation of antithrombin by CS. METHODS AND RESULTS: Advanced type IV atherosclerotic lesions prone to thrombosis contained CSPG (versican) with undersulfated CS relative to CS of the adjacent healthy aorta. Approximately 11% of the CS disaccharide in versican from healthy arteries was oversulfated, but this proportion decreased markedly to 3% in atherosclerotic lesions. Oversulfated CS functionally bound antithrombin with a dissociation constant of 3.3+/-1.9 micromol/L. Measured by osmotic stress (OS) techniques with an approximately 26-A probe, the reaction was linked to transfer of approximately 2500 mol water per mole of coagulation factor Xa inhibited. Under OS, the anticoagulant efficiency of CS was 1.3 (micromol/L)(-1) x s(-1), approximately 5- and 15-fold higher than heparan sulfate efficiency measured under OS and standard conditions, respectively. CONCLUSIONS: Decreased sulfation of high molecular weight CSPG in the advancing atherosclerotic lesions may predispose the lesions to thrombosis by disrupting osmotic regulation, limiting avidity for antithrombin and decreasing activation efficiency.
OBJECTIVE: Changes in chondroitin sulfate (CS) proteoglycan (PG) during atherosclerosis are associated with chronic inflammatory changes and increased incidence of thrombosis. To explore how glycosaminoglycan changes could influence the thrombogenicity of atherosclerotic lesions, water-transfer reactions were examined during activation of antithrombin by CS. METHODS AND RESULTS: Advanced type IV atherosclerotic lesions prone to thrombosis contained CSPG (versican) with undersulfated CS relative to CS of the adjacent healthy aorta. Approximately 11% of the CS disaccharide in versican from healthy arteries was oversulfated, but this proportion decreased markedly to 3% in atherosclerotic lesions. Oversulfated CS functionally bound antithrombin with a dissociation constant of 3.3+/-1.9 micromol/L. Measured by osmotic stress (OS) techniques with an approximately 26-A probe, the reaction was linked to transfer of approximately 2500 mol water per mole of coagulation factor Xa inhibited. Under OS, the anticoagulant efficiency of CS was 1.3 (micromol/L)(-1) x s(-1), approximately 5- and 15-fold higher than heparan sulfate efficiency measured under OS and standard conditions, respectively. CONCLUSIONS: Decreased sulfation of high molecular weight CSPG in the advancing atherosclerotic lesions may predispose the lesions to thrombosis by disrupting osmotic regulation, limiting avidity for antithrombin and decreasing activation efficiency.
Authors: Matthew Ndonwi; Oname O Burlingame; Aaron S Miller; Douglas M Tollefsen; George J Broze; Daniel E Goldberg Journal: Blood Date: 2011-04-21 Impact factor: 22.113