Abstract
The functional state of the circadian system of spontaneously hypertensive rats (SHR) differs in several characteristics from the functional state of normotensive Wistar rats. Some of these changes might be due to the compromised ability of the central pacemaker to entrain the peripheral clocks. Daily body temperature cycles represent one of the important cues responsible for the integrity of the circadian system, because these cycles are driven by the central pacemaker and are able to entrain the peripheral clocks. This study tested the hypothesis that the aberrant peripheral clock entrainment of SHR results from a compromised peripheral clock sensitivity to the daily temperature cycle resetting. Using cultured Wistar rat and SHR fibroblasts transfected with the circadian luminescence reporter Bmal1-dLuc, we demonstrated that two consecutive square-wave temperature cycles with amplitudes of 2.5°C are necessary and sufficient to restart the dampened oscillations and entrain the circadian clocks in both Wistar rat and SHR fibroblasts. We also generated a phase response curve to temperature cycles for fibroblasts of both rat strains. Although some of the data suggested a slight resistance of SHR fibroblasts to temperature entrainment, we concluded that the overall effect it too weak to be responsible for the differences between the SHR and Wistar in vivo circadian phenotype.
Highlights
Circadian rhythms are physiological and behavioral cycles that repeat with a circadian period
To test the needed prerequisites to restart the damped oscillation of Wistar rat and spontaneously hypertensive rats (SHR) fibroblasts transfected with the Bmal1-dLuc reporter, we replaced the growth medium with the recording medium plus 10% serum and immediately placed the fibroblasts into the Lumicycle at a stable 36uC
The administration of a 12-h 38.5uC temperature pulse was not able to restart the oscillations in either Wistar rat or SHR fibroblasts (Fig. 1A)
Summary
Circadian rhythms are physiological and behavioral cycles that repeat with a circadian (i.e., about daily) period They are generated by an endogenous mechanism, anticipate regular changes in environment and adapt the organism to these changes. A second feedback loop is formed by two REV-ERB and three ROR proteins, whose expression is activated by E-boxes and the CLOCK-BMAL1 complex, and after translation and translocation to the nucleus, both the REV-ERB and ROR proteins bind to RORE elements in the Bmal promoter and rhythmically switch on and off the expression of Bmal1 [9,10] Several clock genes, such as Per, RevErba and Bmal, are expressed with a high amplitude circadian rhythm, which can be used to analyze the rhythms in vitro and in vivo
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