title: Inhibition of Rho-kinase by fasudil attenuated angiotensin II-induced cardiac hypertrophy in apolipoprotein E deficient mice.
abstract: 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.
authors.affiliation: Department of Pharmacology, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, USA. jim_wang@berlex.com
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Wang
authors.forename: Valdeci
authors.initials: V
authors.lastname: da Cunha
authors.forename: Baby
authors.initials: B
authors.lastname: Martin-McNulty
authors.forename: Jon
authors.initials: J
authors.lastname: Vincelette
authors.forename: Weiwei
authors.initials: W
authors.lastname: Li
authors.forename: David F
authors.initials: DF
authors.lastname: Choy
authors.forename: Meredith
authors.initials: M
authors.lastname: Halks-Miller
authors.forename: Mithra
authors.initials: M
authors.lastname: Mahmoudi
authors.forename: Miriam
authors.initials: M
authors.lastname: Schroeder
authors.forename: Anthony
authors.initials: A
authors.lastname: Johns
authors.forename: David R
authors.initials: DR
authors.lastname: Light
authors.forename: William P
authors.initials: WP
authors.lastname: Dole
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D024061:Collagen Type III / Q000235:genetics; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis / Q000517:prevention & control; D015870:Gene Expression / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D054460:rho-Associated Kinases
chemical_list: D001057:Apolipoproteins E; D024061:Collagen Type III; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D000804:Angiotensin II; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D009320:Atrial Natriuretic Factor; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C049347:fasudil