Long-term treatment with a specific Rho-kinase inhibitor suppresses cardiac allograft vasculopathy in mice.
Cardiac allograft vasculopathy (CAV) continues to be a major cause of late graft failure after cardiac transplantation. We have demonstrated that Rho-kinase, an effector of the small GTPase Rho, plays an important role in the pathogenesis of arteriosclerosis. In this study, we examined whether the Rho-kinase-mediated pathway is also involved in the pathogenesis of CAV using a specific Rho-kinase inhibitor and a dominant-negative Rho-kinase. Hearts from AKR mice were heterotopically transplanted to C3H/He (allograft) or AKR mice (isograft), and the effects of long-term oral treatment with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil, on CAV were examined at 2 and 4 weeks after the transplantation. Coronary remodeling in the allografts characterized by intimal thickening and perivascular fibrosis was dose-dependently suppressed in the fasudil group compared with the control group (P<0.01, n=9 to 10). The inhibitory effects of hydroxyfasudil were mimicked by in vivo gene transfer of dominant-negative Rho-kinase (P<0.05, n=4). Among the proinflammatory cytokines examined, those of macrophage migration inhibitory factor, interferon-gamma, and transforming growth factor-beta1 were upregulated in the control group and were dose-dependently inhibited in the fasudil group (P<0.01, n=5). Vascular inflammation in the allografts, as evidenced by accumulation of inflammatory cells (macrophages and T cells), was also significantly inhibited in the fasudil group (P<0.05, n=5 to 10). These results indicate that long-term treatment with fasudil suppresses CAV in mice, suggesting that Rho-kinase is an important therapeutic target for the prevention of CAV.
Hattori
Tsuyoshi
T
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences Fukuoka, Japan 812-8582.
Shimokawa
Hiroaki
H
Higashi
Midoriko
M
Hiroki
Junko
J
Mukai
Yasushi
Y
Kaibuchi
Kozo
K
Takeshita
Akira
A
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002465:Cell Movement; D003324:Coronary Artery Disease / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005822:Genetic Vectors; D006083:Graft Occlusion, Vascular / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016027:Heart Transplantation / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D051379:Mice; D008806:Mice, Inbred AKR; D008809:Mice, Inbred C3H; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D054460:rho-Associated Kinases
D016207:Cytokines; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C049347:fasudil