Restoration of CREB function is linked to completion and stabilization of adaptive cardiac hypertrophy in response to exercise

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

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

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 proliferatoractivated receptor-γ 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.

Original languageEnglish (US)
Pages (from-to)H246-H259
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume293
Issue number1
DOIs
StatePublished - Jul 1 2007
Externally publishedYes

Keywords

  • Apoptosis
  • Cyclic-nucleotide regulatory element binding protein
  • Exercise
  • Mitochondria

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Watson, P. A., Reusch, J. E. B., McCune, S. A., Leinwand, L. A., Luckey, S. W., Konhilas, J. P., Brown, D. A., Chicco, A. J., Sparagna, G. C., Long, C. S., & Moore, R. L. (2007). Restoration of CREB function is linked to completion and stabilization of adaptive cardiac hypertrophy in response to exercise. American Journal of Physiology - Heart and Circulatory Physiology, 293(1), H246-H259. https://doi.org/10.1152/ajpheart.00734.2006