Novel regulation of cardiac force-frequency relation by CREM (cAMP response element modulator).
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.
Isoda
Takayoshi
T
Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA.
Paolocci
Nazareno
N
Haghighi
Kobra
K
Wang
Congrong
C
Wang
Yibin
Y
Georgakopoulos
Dimitrios
D
Servillo
Giuseppe
G
Della Fazia
Maria Agnese
MA
Kranias
Evangelia G
EG
Depaoli-Roach
Anna A
AA
Sassone-Corsi
Paolo
P
Kass
David A
DA
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006321:Heart / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D012097:Repressor Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban
D000318:Adrenergic beta-Agonists; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D051786:Cyclic AMP Response Element Modulator; D004268:DNA-Binding Proteins; D007545:Isoproterenol; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D012097:Repressor Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban