Physicochemical Aspects of Heparin Cofactor IIa

Pratt, Charlotte W.; Whinna, Herbert C.; Meade, J. B.; Treanor, Rita E.; Church, Frank C.

doi:10.1111/j.1749-6632.1989.tb22494.x

Cited by 49 publications

(24 citation statements)

References 80 publications

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“…The K d of 212 nM (Fig. 4) was measured for medium molecular weight 125 I-tyramine-heparin (excluding the ϳ12% of molecules lowest in M r as well as the ϳ12% highest in M r and chosen as representative of the "average" heparin molecule), which compares favorably with a previously reported K d of 230 nM for unfractionated heparin and HCII (8). Four aortic DSPG samples with different HCII activities and porcine skin DS were next analyzed by ACE.…”

Section: Differences In Dspg Activity In Thrombin-hcii Assays Correlasupporting

confidence: 73%

“…DS accelerates the HCII-thrombin inhibition reaction in a dose-dependent manner (7,8). Therefore, a rigorous comparison of the activity of GAG or PG in thrombin-HCII inhibition reactions requires that the assays be performed with equimolar concentrations of DSPG/DS.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, changes in arterial DSPG may occur in the human atherosclerotic plaque but have not been reported. DS chains (7,8) and DSPG (9,10) greatly increase the rate of thrombin inhibition by heparin cofactor II (HCII). Thrombin is an enzyme with procoagulant (11), chemoattractant (12, 13), and mitogenic activities (14,15) that is generated at sites of vascular injury.…”

mentioning

confidence: 99%

“…HCII, a glycosaminoglycan (GAG)-binding plasma proteinase inhibitor and member of the serpin superfamily of proteins (19), inhibits thrombin by forming an inactive bimolecular complex with the enzyme. The inhibition re-action is accelerated by DS or DSPG (through the DS moiety) in a dose-dependent manner, up to several thousand-fold at optimal concentrations (7,8). A specific DS hexasaccharide sequence composed of repeats of iduronic acid 2-sulfate 3 Nacetylgalactosamine 4-sulfate has been shown to bind to HCII (20).…”

mentioning

confidence: 99%

“…Given the selectivity with which DS activates HCII among all of the GAG-binding serpins and the presence of DSPG in the extracellular matrix of a wide variety of tissues, HCII has been proposed to be an inhibitor of "extravascular" thrombin activity (i.e. released or generated outside the circulation due to vascular damage) and to be activated physiologically by DSPG (7)(8)(9)(10). Isolated biglycan and decorin from skin and cartilage have been shown to accelerate thrombin-HCII inhibition reactions (10).…”

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confidence: 99%

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Altered Dermatan Sulfate Structure and Reduced Heparin Cofactor II-stimulating Activity of Biglycan and Decorin from Human Atherosclerotic Plaque

Shirk¹,

Parthasarathy²,

Antonio³

et al. 2000

Journal of Biological Chemistry

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Biglycan and decorin are small dermatan sulfate-containing proteoglycans in the extracellular matrix of the artery wall. The dermatan sulfate chains are known to stimulate thrombin inhibition by heparin cofactor II (HCII), a plasma proteinase inhibitor that has been detected within the artery wall. The purpose of this study was to analyze the HCII-stimulatory activity of biglycan and decorin isolated from normal human aorta and atherosclerotic lesions type II through VI and to correlate activity with dermatan sulfate chain composition and structure. Biglycan and decorin from plaque exhibited a 24 -75% and 38 -79% loss of activity, respectively, in thrombin-HCII inhibition assays relative to proteoglycan from normal aorta. A significant negative linear relationship was observed between lesion severity and HCII stimulatory activity (r ‫؍‬ 0.79, biglycan; r ‫؍‬ 0.63, decorin; p < 0.05). Biglycan, but not decorin, from atherosclerotic plaque contained significantly reduced amounts of iduronic acid and disulfated disaccharides ⌬Di-2,4S and ⌬Di-4,6S relative to proteoglycan from normal artery. Affinity coelectrophoresis analysis of a subset of samples demonstrated that increased interaction of proteoglycan with HCII in agarose gels paralleled increased activity in thrombin-HCII inhibition assays. In conclusion, both biglycan and decorin from atherosclerotic plaque possessed reduced activity with HCII, but only biglycan demonstrated a correlation between activity and specific glycosaminoglycan structural features. Loss of the ability of biglycan and decorin in atherosclerotic lesions to regulate thrombin activity through HCII may be critical in the progression of the disease.Biglycan and decorin are small leucine-rich dermatan sulfate (DS) 1 -containing proteoglycans (PGs) found in the extracellular matrix of connective tissues such as skin, bone, and cartilage. Biglycan and decorin have also been detected in the artery wall (1). They are composed of distinct core proteins linked to one (decorin) or two (biglycan) DS chains (2) that consist of alternating hexuronic acid and N-acetylgalactosamine residues. The DS chains are heterogeneous in the extent of posttranslational modifications such as the conversion of glucuronic acid to its epimer iduronic acid and sulfation at the C-4 and C-6 positions of N-acetylgalactosamine and the C-2 position of iduronic acid (3). The predominant disaccharide in mammalian DS is hexuronic acid-N-acetylgalactosamine-4-sulfate, but small amounts of "oversulfated" disaccharides containing two or three sulfates are also usually detectable. Numerous structural studies have been carried out on DS from mucosa, skin, and cartilage. The chain composition appears to be distinct for specific tissues and species (2, 4). However, relatively little is known about the structure of human arterial DSPG in health or disease. DS content is elevated in atherosclerotic plaque compared with normal aorta (5), and DSPGs produced by cultured aortic smooth muscle cells exhibit altered sulfation patterns after trea...

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Section: Differences In Dspg Activity In Thrombin-hcii Assays Correlasupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Altered Dermatan Sulfate Structure and Reduced Heparin Cofactor II-stimulating Activity of Biglycan and Decorin from Human Atherosclerotic Plaque

Shirk¹,

Parthasarathy²,

Antonio³

et al. 2000

Journal of Biological Chemistry

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Anticoagulant activity of dextran derivatives

Raucourt

Mauray

Chaubet³

et al. 1998

J. Biomed. Mater. Res.

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Carboxymethyl dextran benzylamide sulfonate/sulfates (CMDBS) are synthetic polysaccharides with anticoagulant activity. We synthesized eight different highly substituted CMDBS and one CMDSu. We studied both their anticoagulant activity and the catalysis of thrombin (T) inhibition by heparin cofactor II (HCII) and antithrombin (AT) in the presence of these dextran derivatives relative to heparin and dextran sulfate (DXSu). The anticoagulant activity of CMDBS was due both to direct thrombin inhibition and to catalysis of thrombin inhibition by HCII. The anticoagulant and catalytic activities of CMDBS were related mainly to their molecular weight and sulfate content. The interaction of the dextran derivatives with thrombin does not involve the active site of the enzyme. A kinetic study showed that all the CMDBS exhibited higher affinity for thrombin than heparin did but lower affinity than DXSu did, suggesting that the benzylamide and sulfate groups potentiate the interaction between the dextran derivatives and thrombin. This study shows that the mechanism by which the dextran derivatives inhibit thrombin is original and is related to preferential interaction with thrombin; this both inhibits the clotting activity of the enzyme and increases the reaction rate of thrombin inhibition by HCII.

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Low Molecular Weight Heparins: An Emerging New Class of Glycosaminoglycan Antithrombotics

Freedman¹

1991

The Journal of Clinical Pharma

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Physicochemical Aspects of Heparin Cofactor IIa

Cited by 49 publications

References 80 publications

Altered Dermatan Sulfate Structure and Reduced Heparin Cofactor II-stimulating Activity of Biglycan and Decorin from Human Atherosclerotic Plaque

Altered Dermatan Sulfate Structure and Reduced Heparin Cofactor II-stimulating Activity of Biglycan and Decorin from Human Atherosclerotic Plaque

Anticoagulant activity of dextran derivatives

Low Molecular Weight Heparins: An Emerging New Class of Glycosaminoglycan Antithrombotics

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