Humans exhibit marked circadian rhythms in multiple cardiovascular (CV) parameters, including heart rate, cardiac output, and blood pressure. To date, circadian rhythms in physiological CV parameters have been attributed to the same neurohumoral stimuli (e.g. sympathetic activity) believed to be responsible for fatal CV events (e.g. myocardial infarctions, arrhythmias, and sudden cardiac death). Our studies expose a novel molecular mechanism within cardiomyocytes that directly regulates myocardial gene expression, metabolism, and function over the course of the day. This mechanism is the intramyocellular circadian clock. Circadian clocks are transcriptionally-based mechanisms that confer the selective advantage of anticipation, enabling the cardiomyocyte/heart to respond rapidly and appropriately to environmental stimuli upon their onset. The broad objective of this proposal is to test the hypothesis that the circadian clock within the cardiomyocyte synchronizes responsiveness of the heart to the environment, and that impairment of this mechanism results in an inability of the heart to respond appropriately to its environment (i.e. maladaptation). Altered myocardial metabolism plays a central role in the pathogenesis of contractile dysfunction associated with hypertrophic, diabetic, and ischemic heart disease, conditions in which the circadian clock within the cardiomyocyte is impaired. We therefore intend to address the following specific aims: 1) identify the mechanisms by which the circadian clock within the cardiomyocyte modulates myocardial metabolism; and 2) determine the pathophysiological consequences of impairment of the circadian clock within the cardiomyocyte. For these studies, we will utilize our unique mouse model in which the circadian clock is specifically impaired within cardiomyocytes.
For Specific Aim 1, we will utilize isolated working mouse hearts to identify the mechanisms by which the circadian clock within the cardiomyocyte channels fatty acids and glucose into oxidative versus non-oxidative pathways.
For Specific Aim 2, we will investigate whether impairment of the circadian clock within the cardiomyocyte augments ischemia/reperfusion-, diabetes mellitus-, pressure overload-, aging-, and/or simulated shift work- mediated contractile dysfunction. Our long-term objectives are to establish causal links between impairment of the circadian clock within the cardiomyocyte with development of CV disease in humans. ? ? ?
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| Brewer, Rachel A; Collins, Helen E; Berry, Ryan D et al. (2018) Temporal partitioning of adaptive responses of the murine heart to fasting. Life Sci 197:30-39 |
| Peliciari-Garcia, Rodrigo A; Darley-Usmar, Victor; Young, Martin E (2018) An overview of the emerging interface between cardiac metabolism, redox biology and the circadian clock. Free Radic Biol Med 119:75-84 |
| McGinnis, Graham R; Tang, Yawen; Brewer, Rachel A et al. (2017) Genetic disruption of the cardiomyocyte circadian clock differentially influences insulin-mediated processes in the heart. J Mol Cell Cardiol 110:80-95 |
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| Chen, Junqin; Young, Martin E; Chatham, John C et al. (2016) TXNIP regulates myocardial fatty acid oxidation via miR-33a signaling. Am J Physiol Heart Circ Physiol 311:H64-75 |
| Peliciari-Garcia, Rodrigo A; Goel, Mehak; Aristorenas, Jonathan A et al. (2016) Altered myocardial metabolic adaptation to increased fatty acid availability in cardiomyocyte-specific CLOCK mutant mice. Biochim Biophys Acta 1861:1579-95 |
| Young, Martin E (2016) Temporal partitioning of cardiac metabolism by the cardiomyocyte circadian clock. Exp Physiol 101:1035-9 |
| Peliciari-Garcia, Rodrigo Antonio; Prévide, Rafael Maso; Nunes, Maria Tereza et al. (2016) Interrelationship between 3,5,3´-triiodothyronine and the circadian clock in the rodent heart. Chronobiol Int 33:1444-1454 |
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