atrial-natriuretic-factor and fasudil

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.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Atrial Natriuretic Factor; Blotting, Western; Collagen Type I; Collagen Type III; Fibrosis; Male; MAP Kinase Kinase Kinases; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myosin Heavy Chains; Protein Kinase Inhibitors; Random Allocation; Real-Time Polymerase Chain Reaction; rho-Associated Kinases; RNA, Messenger; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta1; Ventricular Remodeling

Recent evidence indicates that the GTPase activated Rho/Rho-kinase pathway contributes angiotensin II-induced cardiac hypertrophy and vascular remodeling. We tested this hypothesis in vivo by determining the effects of fasudil, a Rho-kinase inhibitor, on angiotensin II-induced cardiac hypertrophy, coronary vascular remodeling, and ventricular dysfunction. Six-month-old apolipoprotein E deficient (apoE-KO) mice were subcutaneously infused with angiotensin II (1.44 mg/kg/day) using an osmotic mini-pump. Mice were randomly assigned to either vehicle or fasudil (136 or 213 mg/kg/day in drinking water) group. Infusion of angiotensin II for 4 weeks resulted in cardiac enlargement, myocyte hypertrophy, and myocardial interstitial and coronary artery perivascular fibrosis. These changes were accompanied by reduced aortic flow velocity and acceleration rate. Cardiac gene expression levels of atrial natriuretic peptide (ANP) and collagen type III detected by real-time reverse transcriptase polymerase chain reaction were significantly increased in angiotensin II-infused mice. Treatment with fasudil dose-dependently attenuated angiotensin II-induced cardiac hypertrophy, prevented perivascular fibrosis, blunted the increase in ANP and collagen type III expression, and improved cardiac function, without changing blood pressure. These data are consistent with a role for Rho-kinase activation in angiotensin II-induced cardiac remodeling and vascular wall fibrosis.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Angiotensin II; Animals; Apolipoproteins E; Atrial Natriuretic Factor; Blood Pressure; Cardiomegaly; Collagen Type III; Coronary Vessels; Dose-Response Relationship, Drug; Fibrosis; Gene Expression; Heart Rate; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Knockout; Myocardium; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Reverse Transcriptase Polymerase Chain Reaction; rho-Associated Kinases; RNA, Messenger; Up-Regulation