Rho/Rho-kinase is involved in the synthesis of tissue factor in human monocytes.
Monocytes and macrophages synthesize tissue factor (TF) which plays a role in thrombogenicity in coronary artery disease. This study was conducted to investigate the effect of Rho/Rho-kinase inhibition on the synthesis of TF in cultured human monocytes. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), C3 exoenzyme and Rho-kinase inhibitors were added to isolated peripheral blood monocytes and the synthesis of TF was assessed by reverse transcriptase polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry. Rho activity was determined by measuring the GTP-bound form of Rho A. Cerivastatin and pravastatin reduced the levels of TF antigen and mRNA. The suppressive effect of statins on TF synthesis was reversed by geranylgeranylpyrophosphate (GGPP) and the restoring effect of GGPP was eliminated by C3 exoenzyme and Y-27632. Pravastatin decreased the activity of Rho A, suggesting that the suppression of TF synthesis by statins is mediated via inhibition of the geranylgeranylation of Rho. Moreover, inhibition of Rho and Rho-kinase downregulated the synthesis of TF. Our results suggest that Rho/Rho-kinase signaling is involved in the synthesis of TF in human monocytes and that inhibition of Rho/Rho-kinase may be useful for treating thrombogenicity in coronary artery disease.
Nagata
Kenji
K
First Department of Internal Medicine, Fukushima Medical University, Fukushima, Japan.
Ishibashi
Toshiyuki
T
Sakamoto
Takayuki
T
Ohkawara
Hiroshi
H
Shindo
Joji
J
Yokoyama
Keiko
K
Sugimoto
Koichi
K
Sakurada
Sotaro
S
Takuwa
Yoh
Y
Nakamura
Shin
S
Teramoto
Tamio
T
Maruyama
Yukio
Y
D000214:Acyl Coenzyme A / Q000494:pharmacology*; D000704:Analysis of Variance; D001483:Base Sequence; D015153:Blotting, Western; D002478:Cells, Cultured; D023921:Coronary Stenosis / Q000473:pathology / Q000503:physiopathology; D015536:Down-Regulation; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D007963:Leukocytes, Mononuclear; D008969:Molecular Sequence Data; D017035:Pravastatin / Q000494:pharmacology*; D011336:Probability; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D013925:Thromboplastin / Q000096:biosynthesis / Q000187:drug effects*; D054460:rho-Associated Kinases
D000214:Acyl Coenzyme A; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; D012333:RNA, Messenger; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D013925:Thromboplastin; C086276:cerivastatin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D017035:Pravastatin