title: Pioglitazone attenuates cardiac hypertrophy in rats with salt-sensitive hypertension: role of activation of AMP-activated protein kinase and inhibition of Akt.
abstract: OBJECTIVE
  Cardiac hypertrophy is common in diabetes and an independent risk factor for cardiac morbidity and mortality. We investigated the effects of pioglitazone on cardiac hypertrophy and hypertrophic signaling in Dahl salt-sensitive hypertensive rats.
  
  
  METHODS
  Dahl salt-sensitive rats were fed a high-salt diet from 7 weeks of age and treated with pioglitazone (2.5 mg/kg per day) or vehicle from 7 to 11 weeks.
  
  
  RESULTS
  The vehicle-treated rats developed left ventricular hypertrophy and fibrosis as well as left ventricular diastolic dysfunction. The serum level of adiponectin and the phosphorylation of AMP-activated protein kinase in the myocardium did not differ between the vehicle-treated rats and control rats maintained on a normal diet. The phosphorylation of Akt, mammalian target of rapamycin, and p70S6 kinase as well as the total protein content were increased in the heart of vehicle-treated rats compared with control rats, and these changes were blocked by treatment with pioglitazone. Pioglitazone treatment also ameliorated left ventricular hypertrophy and fibrosis, improved diastolic function, and increased both the serum adiponectin concentration and the level of AMP-activated protein kinase phosphorylation in the heart.
  
  
  CONCLUSIONS
  Long-term administration of pioglitazone attenuated left ventricular hypertrophy and fibrosis as well as inhibited phosphorylation of mammalian target of rapamycin and p70S6 kinase in the heart of hypertensive rats. The beneficial cardiac effects of pioglitazone are likely attributable, at least partly, both to the activation of AMP-activated protein kinase signaling through stimulation of adiponectin secretion and to the inhibition of Akt signaling.
authors.affiliation: Department of Pathophysiology Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Mayuko F
authors.initials: MF
authors.lastname: Kato
authors.forename: Rei
authors.initials: R
authors.lastname: Shibata
authors.forename: Koji
authors.initials: K
authors.lastname: Obata
authors.forename: Masaaki
authors.initials: M
authors.lastname: Miyachi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yazawa
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuboi
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamada
authors.forename: Takao
authors.initials: T
authors.lastname: Nishizawa
authors.forename: Akiko
authors.initials: A
authors.lastname: Noda
authors.forename: Xian Wu
authors.initials: XW
authors.lastname: Cheng
authors.forename: Takashi
authors.initials: T
authors.lastname: Murate
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Koike
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yokota
authors.forename: Kohzo
authors.initials: K
authors.lastname: Nagata
mesh_terms: D055372:AMP-Activated Protein Kinases; D052242:Adiponectin / Q000097:blood; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D003094:Collagen / Q000235:genetics; D004452:Echocardiography; D005355:Fibrosis; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D052242:Adiponectin; C519510:Crtc1 protein, rat; D007004:Hypoglycemic Agents; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D045162:Thiazolidinediones; D014157:Transcription Factors; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D055372:AMP-Activated Protein Kinases; D000077205:Pioglitazone