Long-term inhibition of Rho kinase suppresses intimal thickening in autologous vein grafts in rabbits.
BACKGROUND
Rho kinase plays an important role in vascular smooth muscle cell (VSMC) contraction and other cellular functions, such as proliferation, migration, and apoptosis. Recent studies have demonstrated that long-term inhibition of Rho kinase suppresses coronary artery spasm and vascular lesion formation after arterial injury. In the cardiovascular surgery field, intimal thickening in vein grafts is the major cause of late graft failure, for which no effective treatment has yet been developed. In this study, we examined whether long-term inhibition of Rho kinase suppresses intimal thickening in autologous vein grafts in rabbits.


METHODS
Male rabbits were randomly divided into two groups and received normal chow (control group) or a special chow containing 0.09% fasudil (fasudil group). After oral administration, fasudil is metabolized to a specific Rho kinase inhibitor, hydroxyfasudil. Each group underwent reversed autologous vein graft surgery with the internal jugular vein into the left common carotid artery. At 1, 2, and 4 weeks after the operation, we examined the extent of intimal thickening of the graft and VSMC proliferation and apoptosis.


RESULTS
The intimal thickening was significantly suppressed in the fasudil group compared with the control group at 2 and 4 weeks after the operation. In the fasudil group, VSMC proliferation was suppressed at 1 and 2 weeks after the operation, whereas VSMC apoptosis was enhanced at 2 weeks after the procedure.


CONCLUSIONS
These results indicate that Rho kinase is substantially involved in the pathogenesis of intimal thickening of vein grafts and that it is an important therapeutic target for the prevention of graft failure.
Furuyama
Tadashi
T
Department of Surgery and Science, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan. tfuru@surg2.med.kyushu-u.ac.jp
Komori
Kimihiro
K
Shimokawa
Hiroaki
H
Matsumoto
Yasuharu
Y
Uwatoku
Toyokazu
T
Hirano
Katsuya
K
Maehara
Yoshihiko
Y
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D017536:Carotid Artery, Common / Q000601:surgery*; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins; D007601:Jugular Veins / Q000601:surgery*; D008297:Male; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011817:Rabbits; D011897:Random Allocation; D017539:Tunica Intima / Q000201:enzymology*; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C049347:fasudil