Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension.
BACKGROUND
Direct evidence for Rho-kinase activation in patients with pulmonary hypertension (PH) is still lacking.


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.
Do e
Zhulanqiqige
Z
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan.
Fukumoto
Yoshihiro
Y
Takaki
Aya
A
Tawara
Shunsuke
S
Ohashi
Junko
J
Nakano
Makoto
M
Tada
Tomohiro
T
Saji
Kenya
K
Sugimura
Kohichiro
K
Fujita
Hiroshi
H
Hoshikawa
Yasushi
Y
Nawata
Jun
J
Kondo
Takashi
T
Shimokawa
Hiroaki
H
D000328:Adult; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology* / Q000503:physiopathology; D008168:Lung / Q000098:blood supply*; D008297:Male; D008875:Middle Aged; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology*; D010766:Phosphorylation; D011446:Prospective Studies; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D012720:Severity of Illness Index; D013997:Time Factors; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C515851:ROCK1 protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; C497258:PRKCD protein, human; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D043263:Myosin-Light-Chain Phosphatase