Long-term inhibition of Rho-kinase induces a regression of arteriosclerotic coronary lesions in a porcine model in vivo.
OBJECTIVE
We recently demonstrated that Rho-kinase/ROK/ROCK is functionally upregulated at the arteriosclerotic coronary lesions and plays a key role for coronary vasospastic responses in our porcine model with interleukin (IL)-1beta. In the present study, we tested our hypothesis that Rho-kinase is involved in the pathogenesis of coronary arteriosclerosis per se in our porcine model.


METHODS
Segments of the left porcine coronary artery were chronically treated from the adventitia with IL-1beta. Two weeks after the procedure, coronary stenotic lesions with constrictive remodeling and vasospastic response to serotonin were noted at the IL-1beta-treated site, as previously reported. Then, animals were randomly divided into two groups; one group was treated with fasudil for 8 weeks followed by 1 or 4 weeks of washout period and another group served as a control. After oral absorption, fasudil is metabolized to hydroxyfasudil that is a specific inhibitor of Rho-kinase.


RESULTS
In the fasudil group, coronary stenosis and vasospastic response were progressively reduced in vivo, while the coronary hyperreactivity was abolished both in vivo and in vitro. Furthermore, Western blot analysis showed that in the fasudil group, the Rho-kinase activity (as evaluated by the extent of phosphorylation of myosin binding subunit of myosin phosphatase, one of the major substrates of Rho-kinase) was significantly reduced, while histological examination demonstrated a marked regression of the coronary constrictive remodeling.


CONCLUSIONS
These results indicate that Rho-kinase is substantially involved in constrictive remodeling and vasospastic activity of the arteriosclerotic coronary artery, both of which could be reversed by long-term inhibition of the molecule in vivo. Thus, Rho-kinase may be regarded as a novel therapeutic target for arteriosclerotic vascular disease.
Shimokawa
H
H
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. shimo@cardiol.med.kyushu-u.ac.jp
Morishige
K
K
Miyata
K
K
Kandabashi
T
T
Eto
Y
Y
Ikegaki
I
I
Asano
T
T
Kaibuchi
K
K
Takeshita
A
A
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D017023:Coronary Angiography; D003327:Coronary Disease / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D003329:Coronary Vasospasm / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology; D003331:Coronary Vessels / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D023421:Models, Animal; D005996:Nitroglycerin / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors*; D011897:Random Allocation; D012701:Serotonin / Q000494:pharmacology; D013552:Swine; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D054460:rho-Associated Kinases
D004791:Enzyme Inhibitors; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D014662:Vasoconstrictor Agents; D012701:Serotonin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D005996:Nitroglycerin; C049347:fasudil