Novel regulation of cardiac force-frequency relation by CREM (cAMP response element modulator)

Takayoshi Isoda, Nazareno Paolocci, Kobra Haghighi, Congrong Wang, Yibin Wang, Dimitrios Georgakopoulos, Giuseppe Servillo, Maria Agnese Della Fazia, Evangelia G. Kranias, Anna A. Depaoli-Roach, Paolo Sassone-Corsi, David A. Kass

Research output: Contribution to journalArticle

17 Scopus citations


The cAMP response element modulator (CREM) plays pivotal roles in the hypothalamic-pituitary-gonadal axis. CREM mRNA is robustly expressed in human myocardium, and identified isoforms may suppress cAMP response element-mediated transcription. However, little is known about the physiological importance of CREM in intact hearts remains unknown. We studied CREM-null mice and age-matched control littermates by in vivo pressure-volume loops to analyze basal and reserve cardiac function. Basal systolic and diastolic function, echocardiographic morphology, and myocardial histology were normal in CREM-null animals. However functional reserve with increasing heart rate was markedly depressed, with less contractile augmentation (+22±9% CREM-/- vs.+62±11% controls, P<0.05) and relaxation shortening (5±5% CREM-/- vs. -18±3% controls; P<0.05) at faster rates. In contrast, isoproterenol dose-responses were similar, suggesting normal β-adrenergic receptor-coupled signaling. Gene expression of calcium handling proteins (SERCA, phospholamban) and stress-response genes (e.g., α-skeletal actin, β-myosin heavy chain, natriuretic peptides) were similar between groups. However, total and serine-phosphorylated phospholamban protein declined -38 and -64% respectively, and protein phosphatase-1 (PP1) acfivity increased 44% without increased protein levels (all P<0.01) in CREM-/- vs. controls. These results demonstrate novel involvement of CREM in regulation of PP1 activity and of PLB, likely resulting in a potent frequency-dependent influence on cardiac function.

Original languageEnglish (US)
Pages (from-to)144-151
Number of pages8
JournalFASEB Journal
Issue number2
StatePublished - Feb 1 2003


  • Cardiac function
  • CRE-responsive transcription factor
  • Mouse
  • Phosphatase
  • Phospholamban
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

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    Isoda, T., Paolocci, N., Haghighi, K., Wang, C., Wang, Y., Georgakopoulos, D., Servillo, G., Della Fazia, M. A., Kranias, E. G., Depaoli-Roach, A. A., Sassone-Corsi, P., & Kass, D. A. (2003). Novel regulation of cardiac force-frequency relation by CREM (cAMP response element modulator). FASEB Journal, 17(2), 144-151.