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 De Paoli-Roach, Paolo Sassone-Corsi, David A. Kass

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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
Pages (from-to)144-151
Number of pages8
JournalFASEB Journal
Volume17
Issue number2
DOIs
StatePublished - Feb 1 2003

Fingerprint

response elements
Response Elements
Modulators
Protein Phosphatase 1
phosphoprotein phosphatase
cardiac output
natriuretic peptides
Natriuretic Peptides
Proteins
Histology
proteins
Myosin Heavy Chains
myosin heavy chains
adrenergic receptors
Transcription
myocardium
Isoproterenol
Gene expression
shortenings
Adrenergic Receptors

Keywords

  • 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

Cite this

Isoda, T., Paolocci, N., Haghighi, K., Wang, C., Wang, Y., Georgakopoulos, D., ... Kass, D. A. (2003). Novel regulation of cardiac force-frequency relation by CREM (cAMP response element modulator). FASEB Journal, 17(2), 144-151. https://doi.org/10.1096/fj.01-0981com

Novel regulation of cardiac force-frequency relation by CREM (cAMP response element modulator). / Isoda, Takayoshi; Paolocci, Nazareno; Haghighi, Kobra; Wang, Congrong; Wang, Yibin; Georgakopoulos, Dimitrios; Servillo, Giuseppe; Della Fazia, Maria Agnese; Kranias, Evangelia G.; De Paoli-Roach, Anna; Sassone-Corsi, Paolo; Kass, David A.

In: FASEB Journal, Vol. 17, No. 2, 01.02.2003, p. 144-151.

Research output: Contribution to journalArticle

Isoda, T, Paolocci, N, Haghighi, K, Wang, C, Wang, Y, Georgakopoulos, D, Servillo, G, Della Fazia, MA, Kranias, EG, De Paoli-Roach, A, Sassone-Corsi, P & Kass, DA 2003, 'Novel regulation of cardiac force-frequency relation by CREM (cAMP response element modulator)', FASEB Journal, vol. 17, no. 2, pp. 144-151. https://doi.org/10.1096/fj.01-0981com
Isoda T, Paolocci N, Haghighi K, Wang C, Wang Y, Georgakopoulos D et al. Novel regulation of cardiac force-frequency relation by CREM (cAMP response element modulator). FASEB Journal. 2003 Feb 1;17(2):144-151. https://doi.org/10.1096/fj.01-0981com
Isoda, Takayoshi ; Paolocci, Nazareno ; Haghighi, Kobra ; Wang, Congrong ; Wang, Yibin ; Georgakopoulos, Dimitrios ; Servillo, Giuseppe ; Della Fazia, Maria Agnese ; Kranias, Evangelia G. ; De Paoli-Roach, Anna ; Sassone-Corsi, Paolo ; Kass, David A. / Novel regulation of cardiac force-frequency relation by CREM (cAMP response element modulator). In: FASEB Journal. 2003 ; Vol. 17, No. 2. pp. 144-151.
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