Osmotic stress regulates the anticoagulant efficiency of dermatan sulfate.
Glycosaminoglycans (GAGs) in pericellular and interstitial spaces help to maintain local water homeostasis and blood coagulation balance. This study explored whether dehydrating microenvironment conditions influence dermatan sulfate's (DS) anticoagulant activity. Water transfer during antithrombin activation by dermatan sulfate was measured using osmotic stress techniques. Anticoagulant activity was determined from the change in the rate of coagulation factor Xa (fXa) inhibition. Osmotic stress accelerated reaction rates, indicating water transfer from reactants to bulk. The net volume transferred, measured using osmotic probes similar in size to the reacting proteins, was approximately 2500 mol of water per mole of fXa inhibited. The reaction efficiency, V(sat)/K 1/2 (rate at saturation/concentration resulting in half-maximal rates), determined in titrations with monosulfated dermatan sulfate and disulfated dermatan sulfate (DDS), were 4x10(4) and 2x10(5) M-1 s-1 under osmotic stress and in the presence of calcium, corresponding to 34- and 81-fold increases over efficiency measured under standard conditions. These results indicate that dermatan sulfate can contribute significantly to antithrombin activation, and that in dehydrating environments and depending of ionic conditions, its anticoagulant efficiency can exceed that of heparan sulfate (HS).
McGee
Maria P
MP
Section on Rheumatology, Department of Internal Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. mmcgee@wfubmc.edu
Wagner
William
W
Li
Lynne
L
D020816:Amino Acid Motifs; D000925:Anticoagulants / Q000737:chemistry; D000991:Antithrombins / Q000378:metabolism; D003871:Dermatan Sulfate / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015951:Factor Xa / Q000737:chemistry; D006025:Glycosaminoglycans / Q000737:chemistry; D006493:Heparin / Q000737:chemistry; D006497:Heparan Sulfate / Q000737:chemistry; D006801:Humans; D007477:Ions; D007700:Kinetics; D009995:Osmosis; D013816:Thermodynamics; D013997:Time Factors; D014867:Water / Q000737:chemistry*
D000925:Anticoagulants; D000991:Antithrombins; D003871:Dermatan Sulfate; D015951:Factor Xa; D006025:Glycosaminoglycans; D006493:Heparin; D006497:Heparan Sulfate; D007477:Ions; D014867:Water