The distal carboxyl-terminal domains of ADAMTS13 are required for regulation of in vivo thrombus formation.
ADAMTS13 is a multidomain protease that limits platelet thrombogenesis through the cleavage of von Willebrand factor (VWF). We previously identified 2 types of mouse Adamts13 gene: the 129/Sv-strain Adamts13 gene encodes the long-form ADAMTS13 having the same domains as human ADAMTS13, whereas the C57BL/6-strain Adamts13 gene encodes the short-form ADAMTS13 lacking the distal C-terminal domains. To assess the physiologic significance of the distal C-terminal domains of ADAMTS13, we generated and analyzed 129/Sv-genetic background congenic mice (Adamts13(S/S)) that carry the short-form ADAMTS13. Similar to wild-type 129/Sv mice (Adamts13(L/L)), Adamts13(S/S) did not have ultralarge VWF multimers in plasma, in contrast to 129/Sv-genetic background ADAMTS13-deficient mice (Adamts13(-/-)). However, in vitro thrombogenesis under flow at a shear rate of 5000 s(-1) was accelerated in Adamts13(S/S) compared with Adamts13(L/L). Both in vivo thrombus formation in ferric chloride-injured arterioles and thrombocytopenia induced by collagen plus epinephrine challenge were more dramatic in Adamts13(S/S) than in Adamts13(L/L) but less than in Adamts13(-/-). These results suggested that the C-terminally truncated ADAMTS13 exhibited decreased activity in the cleavage of VWF under high shear rate. Role of the C-terminal domains may become increasingly important under prothrombotic conditions.
Banno
Fumiaki
F
Research Institute, National Cardiovascular Center, Suita, Japan.
Chauhan
Anil K
AK
Kokame
Koichi
K
Yang
Jin
J
Miyata
Shigeki
S
Wagner
Denisa D
DD
Miyata
Toshiyuki
T
D000071120:ADAMTS13 Protein; D000818:Animals; D001160:Arterioles / Q000473:pathology; D002712:Chlorides; D005290:Ferric Compounds / Q000009:adverse effects; D008666:Metalloendopeptidases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D017434:Protein Structure, Tertiary; D013921:Thrombocytopenia / Q000139:chemically induced; D013927:Thrombosis / Q000201:enzymology / Q000209:etiology*; D014841:von Willebrand Factor
D002712:Chlorides; D005290:Ferric Compounds; D014841:von Willebrand Factor; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein; C024555:ferric chloride