The rat heart possesses a fully functional circadian clock. Circadian clocks are intrinsically maintained by molecular mechanisms that condition the cell to changes in its environment. These circadian clocks therefore confer a selective advantage by providing a mechanism for anticipation of change. It is not known, however, which environmental stimuli the circadian clock within the heart anticipates. Diurnal variations in cardiovascular parameters (such as blood pressure, heart rate, and cardiac output) as well as the onset of cardiovascular disease have previously been attributed to neurohumoral factors (e.g. sympathetic activity). In contrast, the second component of stimulus-response coupling, namely the sensitivity of the system to the stimulus, has been largely ignored. The broad objective of this proposal is therefore to test the hypothesis that the circadian clock within the heart synchronizes responsiveness of the heart to diurnal variations in its environmental stimuli, and that impairment of this mechanism results in an inability of the heart to respond appropriately to the onset of such stimuli (i.e. maladaptation). The first specific aim will investigate the potential physiological role(s) of the circadian clock within the heart. Initially we will fully characterize the circadian clock within the heart, utilizing isolated adult rat cardiomyocytes. Next, we will address the nature of the environmental stimuli that the circadian clock allows the heart to anticipate. We intend to investigate whether the rat heart anticipates diurnal variations in substrate availability, workload and/or the energy supply/demand ratio. The second specific aim will address the consequences of impairment of the circadian clock within the heart of rodents due to pressure overload-induced hypertrophy, manipulation of the light/dark cycle, and the generation of a transgenic mouse model with a heart-specific abolition of the circadian clock. Such studies will allow identification of circadian clock-regulated genes in the heart, elucidation of circadian clock-regulated processes in the heart, as well as determination of the consequences of circadian clock impairment on cardiac function. Whether the circadian clock is altered in the failing human heart will also be investigated. Our long-term goals are to establish the molecular mechanisms and physiological role(s) of the circadian clock within the heart, and to determine the pathophysiological consequences of impairment of this mechanism. ? ?
| Peliciari-Garcia, Rodrigo A; Bargi-Souza, Paula; Young, Martin E et al. (2018) Repercussions of hypo and hyperthyroidism on the heart circadian clock. Chronobiol Int 35:147-159 |
| 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 |
| Wende, Adam R; Brahma, Manoja K; McGinnis, Graham R et al. (2017) Metabolic Origins of Heart Failure. JACC Basic Transl Sci 2:297-310 |
| McGinnis, Graham R; Young, Martin E (2016) Circadian regulation of metabolic homeostasis: causes and consequences. Nat Sci Sleep 8:163-80 |
| 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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