Long-term inhibition of Rho-kinase suppresses left ventricular remodeling after myocardial infarction in mice.
BACKGROUND
Rho-kinase has been implicated as an important regulator of inflammatory responses mediated by cytokines and chemokines. Because proinflammatory cytokines play a critical role in left ventricular (LV) remodeling after myocardial infarction (MI), we examined whether long-term blockade of Rho-kinase suppresses LV remodeling in a mouse model of MI in vivo.


RESULTS
Mice underwent ligation of the left coronary artery and were treated with a Rho-kinase inhibitor, fasudil (100 mg x kg(-1) x d(-1) in tap water), for 4 weeks, starting 1 day after the surgery. At 4 weeks, LV infarct size was histologically comparable between the 2 groups. LV cavity dilatation and dysfunction evaluated by echocardiography were significantly suppressed in the fasudil group (P<0.05, n=15 to 28). The beneficial effects of fasudil were accompanied by suppression of cardiomyocyte hypertrophy and interstitial fibrosis (both P<0.01, n=6). The expression of inflammatory cytokines, including transforming growth factor (TGF)-beta2, TGF-beta3, and macrophage migration inhibitory factor, was upregulated in the noninfarcted LV in the control group and was significantly suppressed in the fasudil group (both P<0.05, n=10 to 11). Rho-kinase activity as evaluated by the extent of phosphorylation of the ERM family, a substrate of Rho-kinase, was significantly increased in the noninfarcted LV in the control group and was significantly suppressed in the fasudil group (P<0.05, n=5).


CONCLUSIONS
These results indicate that Rho-kinase is substantially involved in the pathogenesis of LV remodeling after MI associated with upregulation of proinflammatory cytokines, suggesting a therapeutic importance of the molecule for the prevention of post-MI heart failure.
Hattori
Tsuyoshi
T
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Shimokawa
Hiroaki
H
Higashi
Midoriko
M
Hiroki
Junko
J
Mukai
Yasushi
Y
Tsutsui
Hiroyuki
H
Kaibuchi
Kozo
K
Takeshita
Akira
A
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000517:prevention & control*; D019746:Intramolecular Oxidoreductases; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000517:prevention & control*; D020257:Ventricular Remodeling / Q000187:drug effects*
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C513242:Etv5 protein, mouse; D008263:Macrophage Migration-Inhibitory Factors; C509041:TGFB2 protein, human; C509045:Tgfb3 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; C431085:hydroxyfasudil; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse; C049347:fasudil