Evidence for Rho-Kinase Activation in Patients With Pulmonary Arterial Hypertension

被引:123
作者
Do E, Zhulanqiqige
Fukumoto, Yoshihiro
Takaki, Aya
Tawara, Shunsuke
Ohashi, Junko
Nakano, Makoto
Tada, Tomohiro
Saji, Kenya
Sugimura, Kohichiro
Fujita, Hiroshi
Hoshikawa, Yasushi [2 ]
Nawata, Jun
Kondo, Takashi [2 ]
Shimokawa, Hiroaki [1 ]
机构
[1] Tohoku Univ, Grad Sch Med, Dept Cardiovasc Med, Aoba Ku, Sendai, Miyagi 9808574, Japan
[2] Tohoku Univ, Grad Sch Med, Dept Thorac Surg, Sendai, Miyagi 9808574, Japan
关键词
Endothelial function; Pulmonary hypertension; Rho-kinase; Signal transduction; Vascular smooth muscle; SMOOTH-MUSCLE-CELLS; NITRIC-OXIDE SYNTHASE; LONG-TERM INHIBITION; CARDIOVASCULAR MEDICINE; THERAPEUTIC TARGET; CORONARY-ARTERIES; PROTEIN; BOSENTAN; EXPRESSION; FASUDIL;
D O I
10.1253/circj.CJ-09-0135
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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)
引用
收藏
页码:1731 / 1739
页数:9
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