Regulation of extravascular coagulation and fibrinolysis by heparin-dependent mast cell chymase.
We recently characterized a heparin-deficient mouse strain generated by targeting the gene for N-deacetylase/N-sulfotransferase-2 (NDST-2). The NDST-2-/- mice show severe defects in their organization of mast cell (MC) secretory granules, with an almost total absence of the various heparin-binding MC proteases. In the present report we have studied the consequences of heparin/MC protease deficiency for extravascular coagulation and fibrinolysis. Addition of prothrombin to peritoneal cells-a mixture of macrophages, lymphocytes, and MCs-resulted in formation of thrombin but the accumulation of thrombin occurred faster in the NDST-2-/-cells than in normal controls. Further, the generated thrombin was subsequently inactivated in the NDST-2+/+ cell cultures but not in the NDST-2-/- cells. Plasminogen was activated to plasmin at an apparently higher rate in peritoneal cells from NDST-2 null mice than in the normal controls. Similar to thrombin, the generated plasmin was inactivated by NDST-2+/+ but not by the NDST-2-/- cells. Subsequent experiments with normal cells showed that cell surface-associated MC chymase, in a strongly heparin-dependent manner, was responsible for both the thrombin-inactivating- and plasmin-inactivating activities. These results show that MC chymase-heparin complexes have the potential to regulate extravascular coagulation processes, as well as the plasminogen activator/plasmin system.
Tchougounova
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Department of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences, The Biomedical Center, 751 23 Uppsala, Sweden.
Pejler
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D000581:Amidohydrolases / Q000172:deficiency / Q000235:genetics; D000818:Animals; D001777:Blood Coagulation / Q000502:physiology*; D002478:Cells, Cultured; D053818:Chymases; D004151:Dipeptides / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis / Q000502:physiology*; D005838:Genotype; D006493:Heparin / Q000172:deficiency / Q000502:physiology*; D008407:Mast Cells / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D011516:Prothrombin / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D015238:Sulfotransferases / Q000172:deficiency / Q000235:genetics; D013917:Thrombin / Q000378:metabolism; D013997:Time Factors
D004151:Dipeptides; C021129:S 2238; D011516:Prothrombin; D006493:Heparin; D015238:Sulfotransferases; C021350:heparitin sulfotransferase; D012697:Serine Endopeptidases; D053818:Chymases; D013917:Thrombin; D005341:Fibrinolysin; D000581:Amidohydrolases