title: Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension.
abstract: 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.
authors: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan.
authors: Zhulanqiqige
authors: Z
authors: Do e
authors: Yoshihiro
authors: Y
authors: Fukumoto
authors: Aya
authors: A
authors: Takaki
authors: Shunsuke
authors: S
authors: Tawara
authors: Junko
authors: J
authors: Ohashi
authors: Makoto
authors: M
authors: Nakano
authors: Tomohiro
authors: T
authors: Tada
authors: Kenya
authors: K
authors: Saji
authors: Kohichiro
authors: K
authors: Sugimura
authors: Hiroshi
authors: H
authors: Fujita
authors: Yasushi
authors: Y
authors: Hoshikawa
authors: Jun
authors: J
authors: Nawata
authors: Takashi
authors: T
authors: Kondo
authors: Hiroaki
authors: H
authors: Shimokawa
mesh_terms: 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*
chemical_list: 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