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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 and DAVID A. KASS²

Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions,
^* Department of Physiology, University of Maryland, Baltimore, Maryland, USA;
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA;
Department of Biochemistry and Molecular Biology, Indiana University, School of Medicine, Indianapolis, Indiana, USA; and
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS-INSERM-ULP, B.P. 163, 67404 Illkirch-Strasbourg, France

¹Correspondence: Halsted 500, Division of Cardiology, 600 N. Wolfe St., Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA. E-mail: dkass{at}jhmi.edu

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 ß-adrenergic receptor-coupled signaling. Gene expression of calcium handling proteins (SERCA, phospholamban) and stress-response genes (e.g., -skeletal actin, ß-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.—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. Novel regulation of cardiac force-frequency relation by CREM (cAMP response element modulator).

Key Words: CRE-responsive transcription factor • mouse • phosphatase • phospholamban • sarcoplasmic reticulum • cardiac function

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