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 language | English |
|---|---|
| Pages (from-to) | 1731-1739 |
| Number of pages | 9 |
| Journal | Circulation Journal |
| Volume | 73 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 01-09-2009 |
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All Science Journal Classification (ASJC) codes
- Cardiology and Cardiovascular Medicine
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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 journal › Article
TY - JOUR
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.
AB - 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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U2 - 10.1253/circj.CJ-09-0135
DO - 10.1253/circj.CJ-09-0135
M3 - Article
VL - 73
SP - 1731
EP - 1739
JO - Circulation Journal
JF - Circulation Journal
SN - 1346-9843
IS - 9
ER -