Published online before print November 13, 2003, doi: 10.1161/01.RES.0000107196.21335.2B
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on May 28, 2003
Revised on October 14, 2003
Accepted on October 31, 2003
Long-Term Treatment With a Specific Rho-Kinase Inhibitor Suppresses Cardiac Allograft Vasculopathy in Mice
Tsuyoshi Hattori ;
From the Department of Cardiovascular Medicine (T.H., M.H., J.H., Y.M., A.T., H.S.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan, and the Department of Cell Pharmacology (K.K.), Nagoya University Graduate School of Medicine, Nagoya, Japan.
* To whom correspondence should be addressed. E-mail: shimo{at}cardiol.med.kyushu-u.ac.jp.
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-
, and transforming growth factor-
1 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.
Key words: arteriosclerosis • cytokines • transplantation
This article has been cited by other articles:
 |
|
 |
|
  P. Holvoet and P. Sinnaeve Angio-Associated Migratory Cell Protein and Smooth Muscle Cell Migration in Development of Restenosis and Atherosclerosis J. Am. Coll. Cardiol., July 22, 2008; 52(4): 312 - 314. [Full Text] [PDF]
|
|
|
|
 |
|
 P. Rivera, M. P. Ocaranza, S. Lavandero, and J. E. Jalil Rho Kinase Activation and Gene Expression Related to Vascular Remodeling in Normotensive Rats With High Angiotensin I Converting Enzyme Levels Hypertension, October 1, 2007; 50(4): 792 - 798. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Shimokawa and A. Takeshita Rho-Kinase Is an Important Therapeutic Target in Cardiovascular Medicine Arterioscler. Thromb. Vasc. Biol., September 1, 2005; 25(9): 1767 - 1775. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-M. Hyvelin, K. Howell, A. Nichol, C. M. Costello, R. J. Preston, and P. McLoughlin Inhibition of Rho-Kinase Attenuates Hypoxia-Induced Angiogenesis in the Pulmonary Circulation Circ. Res., July 22, 2005; 97(2): 185 - 191. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Nakayama, M. Amano, A. Katsumi, T. Kaneko, S. Kawabata, M. Takefuji, and K. Kaibuchi Rho-kinase and myosin II activities are required for cell type and environment specific migration Genes Cells, February 1, 2005; 10(2): 107 - 117. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Koga, J.-i. Suzuki, H. Kosuge, G. Haraguchi, Y. Onai, H. Futamatsu, Y. Maejima, R. Gotoh, H. Saiki, F. Tsushima, et al. Blockade of the Interaction Between PD-1 and PD-L1 Accelerates Graft Arterial Disease in Cardiac Allografts Arterioscler. Thromb. Vasc. Biol., November 1, 2004; 24(11): 2057 - 2062. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hattori, H. Shimokawa, M. Higashi, J. Hiroki, Y. Mukai, H. Tsutsui, K. Kaibuchi, and A. Takeshita Long-Term Inhibition of Rho-Kinase Suppresses Left Ventricular Remodeling After Myocardial Infarction in Mice Circulation, May 11, 2004; 109(18): 2234 - 2239. [Abstract] [Full Text] [PDF]
|
|