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

Journal Article (Journal Article)

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 beta-adrenergic receptor-coupled signaling. Gene expression of calcium handling proteins (SERCA, phospholamban) and stress-response genes (e.g., alpha-skeletal actin, beta-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) activity 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.

Full Text

Duke Authors

Cited Authors

  • Isoda, T; Paolocci, N; Haghighi, K; Wang, C; Wang, Y; Georgakopoulos, D; Servillo, G; Della Fazia, MA; Kranias, EG; Depaoli-Roach, AA; Sassone-Corsi, P; Kass, DA

Published Date

  • February 2003

Published In

Volume / Issue

  • 17 / 2

Start / End Page

  • 144 - 151

PubMed ID

  • 12554693

Electronic International Standard Serial Number (EISSN)

  • 1530-6860

Digital Object Identifier (DOI)

  • 10.1096/fj.01-0981com

Language

  • eng

Conference Location

  • United States