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Novel regulation of cardiac force-frequency relation by CREM (cAMP response element modulator)
Takayoshi Isoda1, Nazareno Paolocci, Kobra Haghighi
1Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA.
Insights
The cAMP response element modulator (CREM) is crucial for heart function. CREM-null mice showed impaired cardiac function reserve at higher heart rates due to altered phospholamban regulation.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Gene Regulation
Background:
- The cAMP response element modulator (CREM) is implicated in the hypothalamic-pituitary-gonadal axis and expressed in human myocardium.
- While CREM isoforms may inhibit transcription, its physiological role in intact hearts is largely unknown.
Purpose of the Study:
- To investigate the physiological importance of CREM in cardiac function using CREM-null mice.
- To analyze basal and reserve cardiac function, and underlying molecular mechanisms.
Main Methods:
- Utilized in vivo pressure-volume loops to assess cardiac function in CREM-null and control mice.
- Analyzed cardiac morphology, histology, protein expression, and enzyme activity.
Main Results:
- CREM-null mice exhibited normal basal cardiac function but markedly depressed functional reserve at increased heart rates.
- Decreased total and serine-phosphorylated phospholamban protein levels and increased protein phosphatase-1 (PP1) activity were observed in CREM-null hearts.
- Beta-adrenergic receptor signaling and expression of key calcium handling and stress-response genes remained comparable.
Conclusions:
- CREM plays a novel role in regulating cardiac function, particularly its frequency-dependent aspects.
- CREM influences cardiac performance through the modulation of protein phosphatase-1 activity and phospholamban phosphorylation.
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 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.