Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension

Zhulanqiqige Do.e, Yoshihiro Fukumoto, Aya Takaki, Shunsuke Tawara, Junko Ohashi, Makoto Nakano, Tomohiro Tada, Kenya Saji, Kohichiro Sugimura, Hiroshi Fujita, Yasushi Hoshikawa, Jun Nawata, Takashi Kondo, Hiroaki Shimokawa

Research output: Contribution to journalArticle

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Abstract

Background: Direct evidence for Rho-kinase activation in patients with pulmonary hypertension (PH) is still lacking. Methods and Results: Rho-kinase activity in circulating neutrophils was examined by determining the ratio of phosphorylated/total forms of myosin-binding subunit, a substrate of Rho-kinase, in 40 consecutive PH patients and 40 healthy controls. Next, Rho-kinase expression and activity was examined in isolated human lung tissues (5 patients with idiopathic pulmonary arterial hypertension [IPAH], 5 controls) and vascular reactivity of isolated small human pulmonary arteries in vitro (4 IPAH, 4 controls). Rho-kinase activity in circulating neutrophils was significantly increased in the PH patients overall compared with controls (P<0.0001). Significant correlations were noted between Rho-kinase activity and the severity and duration of PAH (all P<0.05). Rho-kinase expression and activity in isolated lung tissues also were significantly increased in the IPAH patients compared with the controls (both P<0.0001). Endothelium-dependent relaxation was markedly impaired and serotonin-induced contraction (in the absence of the endothelium) markedly enhanced in the PAH patients compared with the controls, and the hypercontraction to serotonin was abolished by hydroxyfasudil, a specific Rho-kinase inhibitor. Conclusions: These results provide the first direct evidence for Rho-kinase activation in patients with PAH, suggesting the therapeutic importance of Rho-kinase in the disorder.

Original languageEnglish
Pages (from-to)1731-1739
Number of pages9
JournalCirculation Journal
Volume73
Issue number9
DOIs
Publication statusPublished - 01-09-2009

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rho-Associated Kinases
Pulmonary Hypertension
Endothelium
Serotonin
Neutrophils
Lung
Myosins
Pulmonary Artery
Blood Vessels

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Do.e, Z., Fukumoto, Y., Takaki, A., Tawara, S., Ohashi, J., Nakano, M., ... Shimokawa, H. (2009). Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension. Circulation Journal, 73(9), 1731-1739. https://doi.org/10.1253/circj.CJ-09-0135
Do.e, Zhulanqiqige ; Fukumoto, Yoshihiro ; Takaki, Aya ; Tawara, Shunsuke ; Ohashi, Junko ; Nakano, Makoto ; Tada, Tomohiro ; Saji, Kenya ; Sugimura, Kohichiro ; Fujita, Hiroshi ; Hoshikawa, Yasushi ; Nawata, Jun ; Kondo, Takashi ; Shimokawa, Hiroaki. / Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension. In: Circulation Journal. 2009 ; Vol. 73, No. 9. pp. 1731-1739.
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abstract = "Background: Direct evidence for Rho-kinase activation in patients with pulmonary hypertension (PH) is still lacking. Methods and Results: Rho-kinase activity in circulating neutrophils was examined by determining the ratio of phosphorylated/total forms of myosin-binding subunit, a substrate of Rho-kinase, in 40 consecutive PH patients and 40 healthy controls. Next, Rho-kinase expression and activity was examined in isolated human lung tissues (5 patients with idiopathic pulmonary arterial hypertension [IPAH], 5 controls) and vascular reactivity of isolated small human pulmonary arteries in vitro (4 IPAH, 4 controls). Rho-kinase activity in circulating neutrophils was significantly increased in the PH patients overall compared with controls (P<0.0001). Significant correlations were noted between Rho-kinase activity and the severity and duration of PAH (all P<0.05). Rho-kinase expression and activity in isolated lung tissues also were significantly increased in the IPAH patients compared with the controls (both P<0.0001). Endothelium-dependent relaxation was markedly impaired and serotonin-induced contraction (in the absence of the endothelium) markedly enhanced in the PAH patients compared with the controls, and the hypercontraction to serotonin was abolished by hydroxyfasudil, a specific Rho-kinase inhibitor. Conclusions: These results provide the first direct evidence for Rho-kinase activation in patients with PAH, suggesting the therapeutic importance of Rho-kinase in the disorder.",
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Do.e, Z, Fukumoto, Y, Takaki, A, Tawara, S, Ohashi, J, Nakano, M, Tada, T, Saji, K, Sugimura, K, Fujita, H, Hoshikawa, Y, Nawata, J, Kondo, T & Shimokawa, H 2009, 'Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension', Circulation Journal, vol. 73, no. 9, pp. 1731-1739. https://doi.org/10.1253/circj.CJ-09-0135

Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension. / Do.e, Zhulanqiqige; Fukumoto, Yoshihiro; Takaki, Aya; Tawara, Shunsuke; Ohashi, Junko; Nakano, Makoto; Tada, Tomohiro; Saji, Kenya; Sugimura, Kohichiro; Fujita, Hiroshi; Hoshikawa, Yasushi; Nawata, Jun; Kondo, Takashi; Shimokawa, Hiroaki.

In: Circulation Journal, Vol. 73, No. 9, 01.09.2009, p. 1731-1739.

Research output: Contribution to journalArticle

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T1 - Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension

AU - Do.e, Zhulanqiqige

AU - Fukumoto, Yoshihiro

AU - Takaki, Aya

AU - Tawara, Shunsuke

AU - Ohashi, Junko

AU - Nakano, Makoto

AU - Tada, Tomohiro

AU - Saji, Kenya

AU - Sugimura, Kohichiro

AU - Fujita, Hiroshi

AU - Hoshikawa, Yasushi

AU - Nawata, Jun

AU - Kondo, Takashi

AU - Shimokawa, Hiroaki

PY - 2009/9/1

Y1 - 2009/9/1

N2 - Background: Direct evidence for Rho-kinase activation in patients with pulmonary hypertension (PH) is still lacking. Methods and Results: Rho-kinase activity in circulating neutrophils was examined by determining the ratio of phosphorylated/total forms of myosin-binding subunit, a substrate of Rho-kinase, in 40 consecutive PH patients and 40 healthy controls. Next, Rho-kinase expression and activity was examined in isolated human lung tissues (5 patients with idiopathic pulmonary arterial hypertension [IPAH], 5 controls) and vascular reactivity of isolated small human pulmonary arteries in vitro (4 IPAH, 4 controls). Rho-kinase activity in circulating neutrophils was significantly increased in the PH patients overall compared with controls (P<0.0001). Significant correlations were noted between Rho-kinase activity and the severity and duration of PAH (all P<0.05). Rho-kinase expression and activity in isolated lung tissues also were significantly increased in the IPAH patients compared with the controls (both P<0.0001). Endothelium-dependent relaxation was markedly impaired and serotonin-induced contraction (in the absence of the endothelium) markedly enhanced in the PAH patients compared with the controls, and the hypercontraction to serotonin was abolished by hydroxyfasudil, a specific Rho-kinase inhibitor. Conclusions: These results provide the first direct evidence for Rho-kinase activation in patients with PAH, suggesting the therapeutic importance of Rho-kinase in the disorder.

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Do.e Z, Fukumoto Y, Takaki A, Tawara S, Ohashi J, Nakano M et al. Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension. Circulation Journal. 2009 Sep 1;73(9):1731-1739. https://doi.org/10.1253/circj.CJ-09-0135