Forkhead class O transcription factor 3a activation and Sirtuin1 overexpression in the hypertrophied myocardium of the diabetic Goto-Kakizaki rat.
BACKGROUND
Ventricular remodeling in type 2 diabetes predisposes to fatal coronary heart disease. The proapoptotic forkhead class O transcription factor 3a (FOXO3a) and its modulator, the cardioprotective longevity factor and class III histone deacetylase Sirtuin1 (Sirt1), have been implicated in the regulation of the cardiomyocyte lifespan and hypertrophy.


OBJECTIVE
To examine whether FOXO3a-Sirt1 activation is involved in diabetes-induced cardiomyocyte apoptosis and ventricular hypertrophy.


METHODS
The blood pressure, cardiac functions, cardiomyocyte size, neurohumoral markers, cardiomyocyte apoptosis, nuclear binding of FOXO3a, and Sirt1 expression were determined for 12-week-old spontaneously diabetic Goto-Kakizaki rats and the nondiabetic Wistar control rats.


RESULTS
Goto-Kakizaki rats showed a modest increase in blood pressure, pronounced cardiac hypertrophy, impaired systolic function, and increased plasma brain natriuretic peptide level without changes in plasma renin activity, serum aldosterone or urinary noradrenaline excretion. The cardiomyocyte cross-sectional area was increased by 22%. Phosphorylation of FOXO3a was decreased with a concomitant increase in its nuclear translocation. The myocardial expression of the antiapoptotic FOXO3a modulator Sirt1 was increased two-fold. Acetylation of p53 at the Sirt1-specific lysine 373/382 site was markedly decreased. Myocardial caspase-3 and Bax expression were increased, indicating increased apoptotic signaling; however, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling staining did not reveal any significant increase in cardiomyocyte apoptosis.


CONCLUSIONS
Diabetes-induced cardiac remodeling in Goto-Kakizaki rats is associated with cardiac hypertrophy, systolic dysfunction, increased apoptotic signaling and activation of the FOXO3a pathway. The present study also suggests that antiapoptotic Sirt1 protects against cardiomyocyte apoptosis and acts as a novel regulator of cardiomyocyte growth.
Vahtola
Erik
E
Institute of Biomedicine, Pharmacology, University of Helsinki, Finland.
Louhelainen
Marjut
M
Merasto
Saara
S
Martonen
Essi
E
Penttinen
Satu
S
Aahos
Ilkka
I
Kytö
Ville
V
Virtanen
Ismo
I
Mervaala
Eero
E
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002312:Cardiomyopathy, Hypertrophic / Q000000981:diagnostic imaging / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000503:physiopathology*; D004195:Disease Models, Animal; D004452:Echocardiography; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism*
C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D037761:Sirtuins