Restoration of CREB Function is Linked t ... rtrophy in Response to Exercise

Potential regulation of two factors linked to physiologic outcomes with left ventricular (LV) hypertrophy, resistance to apoptosis and matching of metabolic capacity, by the transcription factor CREB (Cyclic-nucleotide Regulatory Element Binding-protein) was examined in the two models physiological LV hypertrophy; involuntary treadmill running of female Sprague-Dawley rats and voluntary exercise wheel running in female C57Bl/6 mice. Comparative studies were performed in the models of pathologic LV hypertrophy and failure; the Spontaneously Hypertension Heart Failure (SHHF) Rat and the HCM transgenic mouse, a model of familial idiopathic cardiomyopathy. Activating CREB Serine-133 phosphorylation was decreased early in remodeling in response to both physiological (decreased 50-80%) and pathological (decreased 60-80%) hypertrophic stimuli. Restoration of LV CREB phosphorylation occurred concurrent with completion of physiologic hypertrophy (94% of sedentary control) but remained decreased (by 90%) during pathologic hypertrophy. In all models of hypertrophy, CREB phosphorylation/ activation demonstrated strong positive correlations with (1) expression of the anti-apoptotic protein bcl-2 (a CREB-dependent gene) and subsequent reductions in the activation of caspase 9 and caspase 3, (2) expression of PPARgamma-Coactivator-1 (PGC-1, a major regulator of mitochondrial content and respiratory capacity), and (3) LV mitochondrial respiratory rates and mitochondrial protein content. Exercise-induced increases in LV mitochondrial respiratory capacity were commensurate with increases observed in LV mass, as previously reported in the literature. Exercise training of SHHF rats and HCM mice in LV failure improved cardiac phenotype, increased CREB activation (31% and 118%, respectively), increased bcl-2 content, improved apoptotic status and enhanced PGC-1 content and mitochondrial gene expression. Adenovirus-mediated expression of constitutively-active CREB in neonatal rat cardiac recapitulated exercise-induced upregulation of PGC-1 content and mitochondrial oxidative gene expression. These data support a model wherein CREB contributes to physiological hypertrophy by enhancing expression of genes important for efficient oxidative capacity and resistance to apoptosis. Key words: Hypertrophy, Exercise, Mitochondria, Apoptosis, CREB.