title: Cardioprotective effects of pitavastatin on cardiac performance and remodeling in failing rat hearts.
abstract: BACKGROUND
  Activation of phosphatidylinositol 3-kinase (PI3K)-Akt signaling by statins increases the activity of endothelial nitric oxide synthase (eNOS). We investigate whether statins (pitavastatin) improve cardiac function and remodeling via eNOS production associated with the PI3K-Akt signaling pathway, Rho-kinase (ROCK) pathway, and the development of oxidative stress in Dahl salt-sensitive (DS) hypertensive rats with heart failure (DSHF).
  
  
  METHODS
  Pitavastatin (3 mg/kg per day), or pitavastatin plus specific PI3K inhibitor, wortmannin (1 mg/kg per day), or wortmannin alone were administered from the age of 11-18 weeks. Age-matched male Dahl salt-resistant (DR) rats served as a control group.
  
  
  RESULTS
  Decreased end-systolic elastance (Ees) and percent fractional shortening (%FS) in failing rats was significantly ameliorated by pitavastatin, but not pitavastatin plus wortmannin or wortmannin alone. Upregulation of eNOS and Akt phosphorylation by pitavastatin was suppressed by pitavastatin plus wortmannin or wortmannin alone. Pitavastatin effectively inhibited the vascular lesion formation such as medial thickness and perivascular fibrosis, but not pitavastatin plus wortmannin or wortmannin alone. Activated RhoA and myosin light chain phosphorylation and RhoA, ROCK expression was inhibited by pitavastatin or a specific ROCK inhibitor, Y-27632, and downregulated eNOS expression and Akt phosphorylation was ameliorated by Y-27632. Increased expression of NAD(P)H oxidase subunits and activated p65 nuclear factor (NF)-kappaB, p44/p42 extracellular signal-regulated kinases and its downstream effector p90 ribosomal S6 kinase phosphorylation in failing rat hearts was inhibited by pitavastatin.
  
  
  CONCLUSIONS
  These findings suggest that pitavastatin may improve cardiac function and remodeling via eNOS production associated with the PI3K-Akt signaling pathway, the ROCK pathway and oxidative stress.
authors.affiliation: Department of Hypertension and Cardiorenal Medicine, Dokkyo Medical University School of Medicine, Mibu, Japan. nao-koba@dokkyomed.ac.jp
authors.forename: Naohiko
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeshima
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Fukushima
authors.forename: Wataru
authors.initials: W
authors.lastname: Koguchi
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Mamada
authors.forename: Hisato
authors.initials: H
authors.lastname: Hirata
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Machida
authors.forename: Motoo
authors.initials: M
authors.lastname: Shinoda
authors.forename: Noriko
authors.initials: N
authors.lastname: Suzuki
authors.forename: Fumie
authors.initials: F
authors.lastname: Yokotsuka
authors.forename: Kyoko
authors.initials: K
authors.lastname: Tabei
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsuoka
mesh_terms: D000577:Amides / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D020303:Rats, Inbred Dahl; D020257:Ventricular Remodeling / Q000187:drug effects*; D000077191:Wortmannin; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000577:Amides; D000730:Androstadienes; D002316:Cardiotonic Agents; D019255:NADPH Oxidases; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D011804:Quinolines; D000077191:Wortmannin; D020742:rhoA GTP-Binding Protein; C108830:Y 27632; C496316:Nos3 protein, rat; C515768:Cyba protein, rat; C060505:neutrophil cytosolic factor 1; C108475:pitavastatin