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

doi:10.1253/circj.CJ-09-0135

Pulmonary Circulation

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

Author information

Zhulanqiqige Do.e
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
Yoshihiro Fukumoto
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
Aya Takaki
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
Shunsuke Tawara
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
Junko Ohashi
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
Makoto Nakano
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
Tomohiro Tada
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
Kenya Saji
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
Kohichiro Sugimura
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
Hiroshi Fujita
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
Yasushi Hoshikawa
Department of Thoracic Surgery, Tohoku University Graduate School of Medicine
Jun Nawata
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
Takashi Kondo
Department of Thoracic Surgery, Tohoku University Graduate School of Medicine
Hiroaki Shimokawa
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine

Keywords: Endothelial function, Pulmonary hypertension, Rho-kinase, Signal transduction, Vascular smooth muscle

JOURNAL FREE ACCESS

2009 Volume 73 Issue 9 Pages 1731-1739

DOI https://doi.org/10.1253/circj.CJ-09-0135

View "Advance Publication" version (July 9, 2009).

Details

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. (Circ J 2009; 73: 1731-1739)

Corresponding author

Register with J-STAGE for free!