Long-term inhibition of Rho kinase suppresses intimal thickening in autologous vein grafts in rabbits

• Published in: Journal of vascular surgery 2006-06, Vol.43 (6), p.1249-1256
• Main Authors: Furuyama, Tadashi, Komori, Kimihiro, Shimokawa, Hiroaki, Matsumoto, Yasuharu, Uwatoku, Toyokazu, Hirano, Katsuya, Maehara, Yoshihiko
• Format: Article
• Language: English
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - administration & dosage; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology; Analysis of Variance; Animals; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Carotid Artery, Common - surgery; Hormones. Endocrine system; Immunoenzyme Techniques; In Situ Nick-End Labeling; Intracellular Signaling Peptides and Proteins; Jugular Veins - surgery; Male; Medical sciences; Pharmacology. Drug treatments; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Rabbits; Random Allocation; rho-Associated Kinases; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Tunica Intima - enzymology; Vascular surgery: aorta, extremities, vena cava. Surgery of the lymphatic vessels
• ISSN: 0741-5214; 1097-6809
• DOI: 10.1016/j.jvs.2006.02.035

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. 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. 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. 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.