Adenovirus-mediated expression of heparin cofactor II inhibits thrombin-induced cellular responses in fibroblasts and vascular smooth muscle cells.
Heparin cofactor II functions as a physiological inhibitor of thrombin activity. The rate of inactivation of thrombin by heparin cofactor II is increased in the presence of dermatan sulfate, which is produced by fibroblasts or smooth muscle cells. To elucidate the role of heparin cofactor II in the extravascular cells, we induced expression of heparin cofactor II in cultured human fibroblasts or vascular smooth muscle cells using adenovirus-mediated gene transfer. After infection of adenovirus vector, these cells secreted heparin cofactor II protein into culture medium. The expressed heparin cofactor II formed the complex with exogenous thrombin and inhibited the proteolytic activity of thrombin. Expression of heparin cofactor II by infection of adenovirus vector inhibited thrombin-induced tissue-type plasminogen activator and interleukin-6 releases from fibroblasts and thrombin-induced interleukin-6 release from vascular smooth muscle cells. These findings show that fibroblasts and vascular smooth muscle cells expressing heparin cofactor II are resistant to thrombin-induced cellular responses.
Hayakawa
Yumiko
Y
Department of Neurosurgery, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. hayakawa@ms.toyama-mpu.ac.jp
Hirashima
Yutaka
Y
Yamamoto
Hiromichi
H
Hayashi
Nakamasa
N
Kurimoto
Masanori
M
Kuwayama
Naoya
N
Endo
Shunro
S
D000256:Adenoviridae / Q000235:genetics*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects*; D015844:Heparin Cofactor II / Q000008:administration & dosage / Q000235:genetics* / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism; D014161:Transduction, Genetic; D000093242:Interleukin-6 Inhibitors
D015844:Heparin Cofactor II; D015850:Interleukin-6; D013917:Thrombin; D010959:Tissue Plasminogen Activator; D000093242:Interleukin-6 Inhibitors