Long-Term Treatment with a Specific Rho-Kinase Inhibitor Suppresses Cardiac Allograft Vasculopathy in Mice

Tsuyoshi Hattori, Hiroaki Shimokawa, Midoriko Higashi, Junko Hiroki, Yasushi Mukai, Kozo Kaibuchi, Akira Takeshita

Research output: Contribution to journalArticle

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Abstract

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-γ, and transforming growth factor-β1 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.

Original languageEnglish
Pages (from-to)46-52
Number of pages7
JournalCirculation research
Volume94
Issue number1
DOIs
Publication statusPublished - Jan 9 2004

Fingerprint

rho-Associated Kinases
Allografts
Inbred AKR Mouse
Tunica Intima
Isografts
Macrophage Migration-Inhibitory Factors
Dominant Genes
Control Groups
Monomeric GTP-Binding Proteins
Arteriosclerosis
Transforming Growth Factors
Heart Transplantation
Interferons
Blood Vessels
Fibrosis
Transplantation
Macrophages
fasudil
Cytokines
Inflammation

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Hattori, T., Shimokawa, H., Higashi, M., Hiroki, J., Mukai, Y., Kaibuchi, K., & Takeshita, A. (2004). Long-Term Treatment with a Specific Rho-Kinase Inhibitor Suppresses Cardiac Allograft Vasculopathy in Mice. Circulation research, 94(1), 46-52. https://doi.org/10.1161/01.RES.0000107196.21335.2B

Long-Term Treatment with a Specific Rho-Kinase Inhibitor Suppresses Cardiac Allograft Vasculopathy in Mice. / Hattori, Tsuyoshi; Shimokawa, Hiroaki; Higashi, Midoriko; Hiroki, Junko; Mukai, Yasushi; Kaibuchi, Kozo; Takeshita, Akira.

In: Circulation research, Vol. 94, No. 1, 09.01.2004, p. 46-52.

Research output: Contribution to journalArticle

Hattori, T, Shimokawa, H, Higashi, M, Hiroki, J, Mukai, Y, Kaibuchi, K & Takeshita, A 2004, 'Long-Term Treatment with a Specific Rho-Kinase Inhibitor Suppresses Cardiac Allograft Vasculopathy in Mice', Circulation research, vol. 94, no. 1, pp. 46-52. https://doi.org/10.1161/01.RES.0000107196.21335.2B
Hattori, Tsuyoshi ; Shimokawa, Hiroaki ; Higashi, Midoriko ; Hiroki, Junko ; Mukai, Yasushi ; Kaibuchi, Kozo ; Takeshita, Akira. / Long-Term Treatment with a Specific Rho-Kinase Inhibitor Suppresses Cardiac Allograft Vasculopathy in Mice. In: Circulation research. 2004 ; Vol. 94, No. 1. pp. 46-52.
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