Long-Term Inhibition of Rho-Kinase Suppresses Neointimal Formation after Stent Implantation in Porcine Coronary Arteries: Involvement of Multiple Mechanisms

Yasuharu Matsumoto, Toyokazu Uwatoku, Keiji Oi, Kohtaro Abe, Tsuyoshi Hattori, Kunio Morishige, Yasuhiro Eto, Yoshihiro Fukumoto, Kei Ichiro Nakamura, Yosaburo Shibata, Takehisa Matsuda, Akira Takeshita, Hiroaki Shimokawa

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

Objective-We recently demonstrated that Rho-kinase, an effector of the small GTPase Rho, is substantially involved in the pathogenesis of arteriosclerosis. In this study, we examined whether Rho-kinase is also involved in in-stent restenosis and if so, what mechanism is involved. Methods and Results-Pigs underwent stent implantation in the left coronary artery with or without administration of fasudil (30 mg/kg per day orally), a specific Rho-kinase inhibitor, starting 2 days before the procedure for a duration of 4 weeks. On day 28, reductions in coronary diameter and neointimal formation associated with macrophage accumulation, collagen deposition, and transforming growth factor (TGF)-β1 expression were noted at the stent site, and all were significantly suppressed by fasudil. On day 7, fasudil significantly increased the frequency of TUNEL-positive apoptotic cells, while it tended to reduce that of bromodeoxyuridine-positive proliferating cells in the neointima. Western blot analysis on day 7 demonstrated that phosphorylations of the ezrin/radixin/moesin family (a marker of Rho-kinase activity in vivo) and protein expression of monocyte chemoattractant protein-land bcl-2 were upregulated at the stent site and were significantly suppressed by fasudil. Conclusions-These results indicate that long-term inhibition of Rho-kinase suppresses in-stent neointimal formation by multiple mechanisms, including reduced vascular inflammation, enhanced apoptosis, and decreased collagen deposition.

Original languageEnglish
Pages (from-to)181-186
Number of pages6
JournalArteriosclerosis, thrombosis, and vascular biology
Volume24
Issue number1
DOIs
Publication statusPublished - Jan 1 2004

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rho-Associated Kinases
Stents
Coronary Vessels
Swine
Monocyte Chemoattractant Proteins
Collagen
Neointima
Monomeric GTP-Binding Proteins
Arteriosclerosis
In Situ Nick-End Labeling
Transforming Growth Factors
Bromodeoxyuridine
Blood Vessels
Western Blotting
Macrophages
Phosphorylation
Apoptosis
Inflammation
fasudil
Proteins

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Long-Term Inhibition of Rho-Kinase Suppresses Neointimal Formation after Stent Implantation in Porcine Coronary Arteries : Involvement of Multiple Mechanisms. / Matsumoto, Yasuharu; Uwatoku, Toyokazu; Oi, Keiji; Abe, Kohtaro; Hattori, Tsuyoshi; Morishige, Kunio; Eto, Yasuhiro; Fukumoto, Yoshihiro; Nakamura, Kei Ichiro; Shibata, Yosaburo; Matsuda, Takehisa; Takeshita, Akira; Shimokawa, Hiroaki.

In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 24, No. 1, 01.01.2004, p. 181-186.

Research output: Contribution to journalArticle

Matsumoto, Y, Uwatoku, T, Oi, K, Abe, K, Hattori, T, Morishige, K, Eto, Y, Fukumoto, Y, Nakamura, KI, Shibata, Y, Matsuda, T, Takeshita, A & Shimokawa, H 2004, 'Long-Term Inhibition of Rho-Kinase Suppresses Neointimal Formation after Stent Implantation in Porcine Coronary Arteries: Involvement of Multiple Mechanisms', Arteriosclerosis, thrombosis, and vascular biology, vol. 24, no. 1, pp. 181-186. https://doi.org/10.1161/01.ATV.0000105053.46994.5B
Matsumoto, Yasuharu ; Uwatoku, Toyokazu ; Oi, Keiji ; Abe, Kohtaro ; Hattori, Tsuyoshi ; Morishige, Kunio ; Eto, Yasuhiro ; Fukumoto, Yoshihiro ; Nakamura, Kei Ichiro ; Shibata, Yosaburo ; Matsuda, Takehisa ; Takeshita, Akira ; Shimokawa, Hiroaki. / Long-Term Inhibition of Rho-Kinase Suppresses Neointimal Formation after Stent Implantation in Porcine Coronary Arteries : Involvement of Multiple Mechanisms. In: Arteriosclerosis, thrombosis, and vascular biology. 2004 ; Vol. 24, No. 1. pp. 181-186.
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AU - Matsumoto, Yasuharu

AU - Uwatoku, Toyokazu

AU - Oi, Keiji

AU - Abe, Kohtaro

AU - Hattori, Tsuyoshi

AU - Morishige, Kunio

AU - Eto, Yasuhiro

AU - Fukumoto, Yoshihiro

AU - Nakamura, Kei Ichiro

AU - Shibata, Yosaburo

AU - Matsuda, Takehisa

AU - Takeshita, Akira

AU - Shimokawa, Hiroaki

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N2 - Objective-We recently demonstrated that Rho-kinase, an effector of the small GTPase Rho, is substantially involved in the pathogenesis of arteriosclerosis. In this study, we examined whether Rho-kinase is also involved in in-stent restenosis and if so, what mechanism is involved. Methods and Results-Pigs underwent stent implantation in the left coronary artery with or without administration of fasudil (30 mg/kg per day orally), a specific Rho-kinase inhibitor, starting 2 days before the procedure for a duration of 4 weeks. On day 28, reductions in coronary diameter and neointimal formation associated with macrophage accumulation, collagen deposition, and transforming growth factor (TGF)-β1 expression were noted at the stent site, and all were significantly suppressed by fasudil. On day 7, fasudil significantly increased the frequency of TUNEL-positive apoptotic cells, while it tended to reduce that of bromodeoxyuridine-positive proliferating cells in the neointima. Western blot analysis on day 7 demonstrated that phosphorylations of the ezrin/radixin/moesin family (a marker of Rho-kinase activity in vivo) and protein expression of monocyte chemoattractant protein-land bcl-2 were upregulated at the stent site and were significantly suppressed by fasudil. Conclusions-These results indicate that long-term inhibition of Rho-kinase suppresses in-stent neointimal formation by multiple mechanisms, including reduced vascular inflammation, enhanced apoptosis, and decreased collagen deposition.

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