title: Critical role of Rho-kinase pathway for cardiac performance and remodeling in failing rat hearts.
abstract: OBJECTIVE
  Rho and Rho-kinase play a critical role in the regulation of cellular functions such as proliferation and migration. To elucidate the molecular mechanisms that regulate cardiac function and cardiovascular remodeling, we determined whether the signaling pathway through Rho is involved in Dahl salt-sensitive hypertensive rats with congestive heart failure (CHF) using a specific Rho-kinase inhibitor, Y-27632.
  
  
  METHODS
  Y-27632 was administered from the left ventricular hypertrophy stage (11 weeks) to the CHF stage (18 weeks) for 7 weeks. The left ventricular end-systolic pressure-volume relationship (contractility: E(es)) was evaluated using a conductance catheter.
  
  
  RESULTS
  Downregulated E(es) in the CHF stage was significantly ameliorated by Y-27632 treatment. Increased RhoA protein, Rho-kinase gene expression and myosin light chain phosphorylations in CHF rats were suppressed by Y-27632. Upregulated proto-oncogene c-fos gene expression in CHF rats was decreased by inhibiting Rho-kinase. In contrast, Y-27632 showed no effect on upregulated extracellular signal-regulated kinases (ERK) and p70S6 kinase phosphorylations, which were reported to be involved in protein synthesis. In the CHF stage, Y-27632 effectively inhibited vascular lesion formation such as medial thickness and perivascular fibrosis.
  
  
  CONCLUSIONS
  These results suggest that differential activation of the Rho-Rho-kinase and the ERK-p70S6 kinase pathways may play a critical role in CHF, and the Rho-Rho-kinase pathway is involved in the pathogenesis of cardiac dysfunction and cardiovascular remodeling. Thus, inhibition of the Rho-kinase pathway may be at least a potential therapeutic strategy for CHF.
authors.affiliation: Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan. a-fukuda@dokkyomed.ac.jp
authors.forename: Naohiko
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Shigeo
authors.initials: S
authors.lastname: Horinaka
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Mita
authors.forename: Shigefumi
authors.initials: S
authors.lastname: Nakano
authors.forename: Takeaki
authors.initials: T
authors.lastname: Honda
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Yoshida
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsuoka
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006333:Heart Failure / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D023421:Models, Animal; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D018994:Myosin Light Chains / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012234:Rho Factor / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020257:Ventricular Remodeling; D054460:rho-Associated Kinases
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D018994:Myosin Light Chains; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D012234:Rho Factor; C108830:Y 27632; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D054460:rho-Associated Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases