Pioglitazone attenuates cardiac hypertrophy in rats with salt-sensitive hypertension: role of activation of AMP-activated protein kinase and inhibition of Akt.
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.
Kato
Mayuko F
MF
Department of Pathophysiology Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Shibata
Rei
R
Obata
Koji
K
Miyachi
Masaaki
M
Yazawa
Hiroki
H
Tsuboi
Koji
K
Yamada
Takashi
T
Nishizawa
Takao
T
Noda
Akiko
A
Cheng
Xian Wu
XW
Murate
Takashi
T
Koike
Yasuo
Y
Murohara
Toyoaki
T
Yokota
Mitsuhiro
M
Nagata
Kohzo
K
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
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