Forkhead class O transcription factor 3a activation and Sirtuin1 overexpression in the hypertrophied myocardium of the diabetic Goto-Kakizaki rat

Journal of Hypertension
Erik VahtolaEero Mervaala

Abstract

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

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