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(Circulation. 2002;106:3133.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Thrombosis Increases Circulatory Hepatocyte Growth Factor by Degranulation of Mast Cells

From the Department of Cardiovascular Medicine, Kyoto University, Kyoto, Japan.

Correspondence to Dr Akira Matsumori, Department of Cardiovascular Medicine, Kyoto University, 54 Kawaracho Shogoin, Sakyo-ku, Kyoto 606-8397, Japan. E-mail amat{at}kuhp.kyoto-u.ac.jp

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.

Methods and Results— Wistar rats received through the tail vein (1) normal saline (NS), (2) 50 µg 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.

Key Words: growth substances • heparin • thrombus • cells • thrombosis

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