TY - JOUR
T1 - Novel regulation of cardiac force-frequency relation by CREM (cAMP response element modulator)
AU - Isoda, Takayoshi
AU - Paolocci, Nazareno
AU - Haghighi, Kobra
AU - Wang, Congrong
AU - Wang, Yibin
AU - Georgakopoulos, Dimitrios
AU - Servillo, Giuseppe
AU - Della Fazia, Maria Agnese
AU - Kranias, Evangelia G.
AU - Depaoli-Roach, Anna A.
AU - Sassone-Corsi, Paolo
AU - Kass, David A.
PY - 2003/2/1
Y1 - 2003/2/1
N2 - 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.
AB - 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.
KW - CRE-responsive transcription factor
KW - Cardiac function
KW - Mouse
KW - Phosphatase
KW - Phospholamban
KW - Sarcoplasmic reticulum
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U2 - 10.1096/fj.01-0981com
DO - 10.1096/fj.01-0981com
M3 - Article
C2 - 12554693
AN - SCOPUS:0037308088
SN - 0892-6638
VL - 17
SP - 144
EP - 151
JO - FASEB Journal
JF - FASEB Journal
IS - 2
ER -