Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression
Autor: | Martin E. Young, Chad A. Shaw, David J. Durgan, Heiko Bugger, William J. Jeong, Melissa M. Zanquetta, Jason R.B. Dyck, Michael W. S. Moore, Paul E. Hardin, E. Dale Abel, Ju Yun Tsai, Sheldon E. Litwin, Dongfang Zhang, Rodrigo Antonio Peliciari Garcia, Margaret P. Chandler, Andreas Rohrwasser, Julie H. Rennison, Chi Wing Chow, Molly S. Bray |
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Rok vydání: | 2008 |
Předmět: |
medicine.medical_specialty
Physiology Circadian clock Gene Expression Muscle Proteins In Vitro Techniques Mitochondrion Biology Mitochondria Heart Electrocardiography Mice Heart Rate Physiology (medical) Internal medicine Gene expression medicine Animals Telemetry Myocyte Myocytes Cardiac Circadian rhythm Oligonucleotide Array Sequence Analysis Chronobiology Reverse Transcriptase Polymerase Chain Reaction Myocardium DNA Myocardial Contraction Circadian Rhythm Cardiovascular physiology Cell biology Perfusion Endocrinology Echocardiography Cardiology and Cardiovascular Medicine Function (biology) Signal Transduction |
Zdroj: | American Journal of Physiology-Heart and Circulatory Physiology. 294:H1036-H1047 |
ISSN: | 1522-1539 0363-6135 |
Popis: | Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally based molecular mechanism in cardiovascular biology is poorly understood. We hypothesized that the circadian clock within the cardiomyocyte influences diurnal variations in myocardial biology. We, therefore, generated a cardiomyocyte-specific circadian clock mutant (CCM) mouse to test this hypothesis. At 12 wk of age, CCM mice exhibit normal myocardial contractile function in vivo, as assessed by echocardiography. Radiotelemetry studies reveal attenuation of heart rate diurnal variations and bradycardia in CCM mice (in the absence of conduction system abnormalities). Reduced heart rate persisted in CCM hearts perfused ex vivo in the working mode, highlighting the intrinsic nature of this phenotype. Wild-type, but not CCM, hearts exhibited a marked diurnal variation in responsiveness to an elevation in workload (80 mmHg plus 1 μM epinephrine) ex vivo, with a greater increase in cardiac power and efficiency during the dark (active) phase vs. the light (inactive) phase. Moreover, myocardial oxygen consumption and fatty acid oxidation rates were increased, whereas cardiac efficiency was decreased, in CCM hearts. These observations were associated with no alterations in mitochondrial content or structure and modest mitochondrial dysfunction in CCM hearts. Gene expression microarray analysis identified 548 and 176 genes in atria and ventricles, respectively, whose normal diurnal expression patterns were altered in CCM mice. These studies suggest that the cardiomyocyte circadian clock influences myocardial contractile function, metabolism, and gene expression. |
Databáze: | OpenAIRE |
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