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Am J Physiol Heart Circ Physiol 293: H246-H259, 2007. First published March 2, 2007; doi:10.1152/ajpheart.00734.2006
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Restoration of CREB function is linked to completion and stabilization of adaptive cardiac hypertrophy in response to exercise

Peter A. Watson,1,2 Jane E. B. Reusch,1,2 Sylvia A. McCune,3,4 Leslie A. Leinwand,3,4 Stephen W. Luckey,3 John P. Konhilas,3 David A. Brown,3 Adam J. Chicco,3 Genevieve C. Sparagna,3 Carlin S. Long,1 and Russell L. Moore3

1University of Colorado Health Sciences Center, and 2Denver Veterans Affairs Medical Center, Denver; and 3University of Colorado, and 4Myogen Inc., Boulder, Colorado

Submitted 10 July 2006 ; accepted in final form 27 February 2007

Potential regulation of two factors linked to physiological outcomes with left ventricular (LV) hypertrophy, resistance to apoptosis, and matching of metabolic capacity, by the transcription factor cyclic-nucleotide regulatory element binding protein (CREB), was examined in the two models of 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 pathological LV hypertrophy and failure: the spontaneously hypertension heart failure (SHHF) rat and the hypertrophic cardiomyopathy (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 physiological hypertrophy (94% of sedentary control), but remained decreased (by 90%) during pathological 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 peroxisome proliferator-activated receptor-{gamma} 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.

exercise; mitochondria; apoptosis; cyclic-nucleotide regulatory element binding protein


Address for reprint requests and other correspondence: P. Watson, Denver VA Medical Center, 111H, 1055 Clermont St., Denver CO 80220 (e-mail: pete.watson{at}uchsc.edu)




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