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Molecular basis of Period 1 regulation by adrenergic signaling in the heart. | LitMetric

AI Article Synopsis

  • The cardiac circadian clock influences heart function and its disruption is linked to diseases; the exact mechanisms of how it is regulated remain unclear.
  • The study investigates how noradrenaline (NE) acts as a zeitgeber, showing that it resets the expression of cardiac clock genes, particularly Per1, which has a distinct response during the dark phase related to heart rate increases.
  • The research reveals that β2-adrenergic receptor signaling is crucial for this process, as blocking these receptors prevents the nocturnal rise in Per1, while activation of pathways like PI3Kγ and ERK1/2 promotes Per1 expression, highlighting a complex regulatory mechanism for circadian rhythms in the heart.

Article Abstract

The cardiac circadian clock is responsible for the modulation of different myocardial processes, and its dysregulation has been linked to disease development. How this clock machinery is regulated in the heart remains an open question. Because noradrenaline (NE) can act as a zeitgeber in cardiomyocytes, we tested the hypothesis that adrenergic signaling resets cardiac clock gene expression in vivo. In its anti-phase with Clock and Bmal1, cardiac Per1 abundance increased during the dark phase, concurrent with the rise in heart rate and preceded by an increase in NE levels. Sympathetic denervation altered Bmal1 and Clock amplitude, while Per1 was affected in both amplitude and oscillatory pattern. We next treated mice with a β-adrenergic receptor (β-AR) blocker. Strikingly, the β-AR blockade during the day suppressed the nocturnal increase in Per1 mRNA, without altering Clock or Bmal1. In contrast, activating β-AR with isoproterenol (ISO) promoted an increase in Per1 expression, demonstrating its responsiveness to adrenergic input. Inhibitors of ERK1/2 and CREB attenuated ISO-induced Per1 expression. Upstream of ERK1/2, PI3Kγ mediated ISO induction of Per1 transcription, while activation of β2-AR, but not β1-AR induced increases in ERK1/2 phosphorylation and Per1 expression. Consistent with the β2-induction of Per1 mRNA, ISO failed to activate ERK1/2 and elevate Per1 in the heart of β2-AR mice, whereas a β2-AR antagonist attenuated the nocturnal rise in Per1 expression. Our study established a link between NE/β2-AR signaling and Per1 oscillation via the PI3Ky-ERK1/2-CREB pathway, providing a new framework for understanding the physiological mechanism involved in resetting cardiac clock genes.

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Source
http://dx.doi.org/10.1096/fj.202100441RDOI Listing

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