title: Inhibition of Rho-kinase ameliorates myocardial remodeling and fibrosis in pressure overload and myocardial infarction: role of TGF-β1-TAK1.
abstract: Inhibition of Rho-kinase displays vasodilation property although its effect on cardiac remodeling in heart against pressure overload and ischemia has not been fully elucidated. The present study was designed to examine the effect of fasudil, a Rho-kinase (ROCK) inhibitor, on myocardial remodeling and underlying mechanisms in pressure overload and myocardial infarction (MI) mice. Pressure overload was produced by constriction of the transverse aorta (TAC) for 3 weeks. Left ventricular (LV) geometry, cardiac hypertrophy, fibrosis, and remodeling were evaluated by transthoracic echocardiography and cardiac histology. Expressions of the hypertrophic and profibrotic markers were analyzed in TAC and MI mice with or without fasudil treatment. LV cavity dilatation and dysfunction evaluated by echocardiography were significantly suppressed in the fasudil-treated MI group compared with the MI group (P<0.05); however, there were no significant difference between the TAC group and the fasudil-treated TAC group. Inhibition of ROCK exhibited reduced interstitial fibrosis, which was observed both in TAC and MI mice (P<0.05). The beneficial effects of fasudil were closely associated with the change of the specific profibrotic gene expression and TGF-β1-TAK1 pathway. Taken together, these results indicate that Rho-kinase is substantially involved in the myocardial remodeling after TAC and MI associated with upregulation of profibrotic gene expression and TGF-β1-TAK1 pathway; further suggest the protective effect of fasudil on heart against pathological stimuli by inhibiting reactive fibrosis.
authors.affiliation: Department of Pharmacology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xu
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Li
authors.forename: Yankun
authors.initials: Y
authors.lastname: Guo
authors.forename: Gaolin
authors.initials: G
authors.lastname: Liu
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D009320:Atrial Natriuretic Factor; D024042:Collagen Type I; D024061:Collagen Type III; D020930:MAP Kinase Kinase Kinases; D018995:Myosin Heavy Chains; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D054460:rho-Associated Kinases; D000099151:MAP Kinase Kinase Kinase 7; C049347:fasudil