Thrombosis increases circulatory hepatocyte growth factor by degranulation of mast cells.
BACKGROUND
Plasma concentrations of hepatocyte growth factor (HGF), a powerful angiogenic growth factor inducible by heparin, increase in thrombus-associated disorders such as myocardial infarction and unstable angina. The mechanism of this thrombus-associated HGF release, however, is unknown.


RESULTS
Wistar rats received through the tail vein (1) normal saline (NS), (2) 50 micro g of the mast cell-degranulating agent CP48/80, or (3) 1000 U/kg heparin. Blood samples were collected at 10 minutes or 30 minutes after the injections, or from untreated rats, for measurements of HGF. The same experiments were performed in mast cell-deficient white spotting (Ws) rats. Ws rats have a small deletion of the c-kit gene and are deficient in mast cells. Intravenous heparin immediately increased plasma HGF in both Wistar (38.02+/-2.08 ng/mL versus 1.11+/-0.70 ng/mL in untreated rats, P<0.0001) and Ws rats (36.39+/-4.15 ng/mL versus 0.66+/-0.18 ng/mL in NS-treated rats, P<0.0001). Injection of CP48/80 also increased plasma HGF in Wistar rats (9.12+/-1.11 ng/mL versus 0.65+/-0.24 ng/mL in NS group, P=0.004) but not in Ws rats (0.67+/-0.27 ng/mL versus 0.66+/-0.18 ng/mL in NS group, P=0.997). In a rat carotid artery microthrombus model, intra-arterial thrombus formation increased circulating HGF in Wistar rats (2.12+/-0.70 ng/mL versus sham 0.61+/-0.15 ng/mL in sham-operated Wistar rats, P=0.0064) but not in Ws rats (0.76+/-0.33 ng/mL versus 0.21+/-0.04 ng/mL in sham-operated Ws rats, P=0.29). In addition, in vitro stimulation of rat peritoneal mast cells with thrombin rapidly induced degranulation in a dose-dependent manner.


CONCLUSIONS
These observations indicate that mast cell degranulation stimulated by thrombin is necessary for the rapid induction of plasma HGF in intravascular thrombus-associated disorders.
Kinoshita
Makoto
M
Department of Cardiovascular Medicine, Kyoto University, Kyoto, Japan.
Miyamoto
Tadashi
T
Ohashi
Naohiro
N
Sasayama
Shigetake
S
Matsumori
Akira
A
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives; D002341:Carotid Artery Thrombosis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D015550:Cell Degranulation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D017228:Hepatocyte Growth Factor / Q000097:blood*; D006632:Histamine / Q000097:blood; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D010875:Pipecolic Acids / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D015424:Reperfusion; D013449:Sulfonamides; D013917:Thrombin / Q000037:antagonists & inhibitors; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
D000925:Anticoagulants; D010875:Pipecolic Acids; D013449:Sulfonamides; D003189:p-Methoxy-N-methylphenethylamine; D017228:Hepatocyte Growth Factor; D006632:Histamine; D001120:Arginine; D019009:Proto-Oncogene Proteins c-kit; D013917:Thrombin; C031942:argatroban