Involvement of rho-kinase in agonists-induced contractions of arteriosclerotic human arteries.
Coronary artery spasm plays an important role in the pathogenesis of a wide variety of ischemic heart diseases. We have recently demonstrated that Rho-kinase plays a key role in the spasm in our porcine model. However, it remains to be elucidated whether Rho-kinase-mediated pathway also contributes to vasoconstriction of human arteries. From 15 patients who underwent coronary artery bypass operation, segments of isolated left internal thoracic arteries were obtained, and the endothelium was gently removed. Serotonin and histamine caused contractions, which were markedly inhibited by a specific Rho-kinase inhibitor, hydroxyfasudil. Western blot analysis showed that, during the serotonin-induced contractions, the extent of phosphorylation of myosin-binding subunit of myosin phosphatase (MBS, one of the major substrates of Rho-kinase) was significantly increased in the specimens. Hydroxyfasudil again significantly suppressed the serotonin-induced increase in MBS phosphorylation. There was a significant positive correlation between the extent of MBS phosphorylation and that of the serotonin-induced contractions and between hydroxyfasudil-sensitive components of the contractions and the extent of arteriosclerosis. These results indicate that Rho-kinase plays an important role in vascular smooth muscle contractions of arteriosclerotic human arteries, suggesting that Rho-kinase could be regarded as an important target for the treatment of arteriosclerotic vascular diseases in humans.
Kandabashi
Tadashi
T
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Shimokawa
Hiroaki
H
Mukai
Yasushi
Y
Matoba
Tetsuya
T
Kunihiro
Ikuko
I
Morikawa
Keiko
K
Ito
Masaaki
M
Takahashi
Shosuke
S
Kaibuchi
Kozo
K
Takeshita
Akira
A
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003324:Coronary Artery Disease / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*; D010749:Phosphoprotein Phosphatases; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D013386:Succinates / Q000494:pharmacology; D013895:Thoracic Arteries / Q000187:drug effects / Q000503:physiopathology; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D054460:rho-Associated Kinases
D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C107507:PPP1R14A protein, human; D010750:Phosphoproteins; D013386:Succinates; D014665:Vasodilator Agents; C431085:hydroxyfasudil; C064294:sarpogrelate; D012701:Serotonin; D006632:Histamine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D010749:Phosphoprotein Phosphatases