Molecular basis of
            <i>Period 1</i>
            regulation by adrenergic signaling in the heart

Jesus, Itamar Couto Guedes de; Araújo, Flávia M.; Mesquita, Thássio; Júnior, Nilton N. S.; Silva, Mário M.; Morgan, Henrique Jorge Novaes; Silva, Kaoma S. C.; Silva, Cleide L. A.; Birbrair, Alexander; Amaral, Flávio Almeida; Navegantes, Luiz Carlos Carvalho; Salgado, Hélio César; Szawka, Raphael E.; Poletini, Maristela O.; Guatimosim, Sílvia

doi:10.1096/fj.202100441r

Cited by 11 publications

(9 citation statements)

References 62 publications

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“…Furthermore, two studies have shown there is no day-night variation in vagal activity [10,11]. However, there is evidence of a day-night rhythm in sympathetic nerve activity [10,12], as well as a day-night rhythm in plasma catecholamines released from the adrenal medulla [13][14][15] and in the catecholamine content of the heart [16]; all are greater during the awake period. Although this potentially could explain the higher resting heart rate during the awake period (via changes in singleion channel conductances), short-term pharmacological autonomic blockade does not block the day-night rhythm in the resting heart rate [1].…”

Section: Introductionmentioning

confidence: 99%

Non-canonical role of the sympathetic nervous system in the day–night rhythm in heart rate

Anderson

Forte

Wei

et al. 2023

Phil. Trans. R. Soc. B

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Although, for many decades, the day–night rhythm in resting heart rate has been attributed to the parasympathetic branch of the autonomic nervous system (high vagal tone during sleep), recently we have shown that there is a circadian clock in the cardiac pacemaker, the sinus node, and the day–night rhythm in heart rate involves an intrinsic rhythmic transcriptional remodelling of pacemaker ion channels, particularly Hcn4 . We have now investigated the role of the sympathetic branch of the autonomic nervous system in this and shown it to have a non-canonical role. In mice, sustained long-term block of cardiac β-adrenergic receptors by propranolol administered in the drinking water abolished the day–night rhythm in pacemaking in the isolated sinus node. Concomitant with this, there was a loss of the normal day–night rhythm in many pacemaker ion channel transcripts. However, there was little or no change in the local circadian clock, indicating that the well-known day–night rhythm in sympathetic nerve activity is directly involved in pacemaker ion channel transcription. The day–night rhythm in pacemaking helps explain the occurrence of clinically significant bradyarrhythmias during sleep, and this study improves our understanding of this pathology. This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.

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Section: Introductionmentioning

confidence: 99%

Non-canonical role of the sympathetic nervous system in the day–night rhythm in heart rate

Anderson

Forte

Wei

et al. 2023

Phil. Trans. R. Soc. B

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“…The beating rate and beating velocity were analyzed using the real-time videos by a custom-coded motion tracking MATLAB program. ISP is a β-adrenergic receptor agonist, which has been demonstrated to increase heart rate . In the absence of ISP, there was no significant difference in the spontaneous beating rate of the hiPSC-CMs cultured on different substrates.…”

Section: Results and Discussionmentioning

confidence: 98%

Aligned Nanofibrous Net Deposited Perpendicularly on Microridges Supports Endothelium Formation and Promotes the Structural Maturation of hiPSC-Derived Cardiomyocytes

Tian

Liang

Lin

et al. 2023

ACS Appl. Mater. Interfaces

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Cell alignment widely exists in various in vivo tissues and also plays an essential role in the construction of in vitro models, such as vascular endothelial and myocardial models. Recently, microscale and nanoscale hierarchical topographical structures have been drawing increasing attention for engineering in vitro cell alignment. In the present study, we fabricated a micro-/nanohierarchical substrate based on soft lithography and electrospinning to assess the synergetic effect of both the aligned nanofibrous topographical guidance and the off-ground culture environment provided by the substrate on the endothelium formation and the maturation of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The morphology, proliferation, and barrier formation of human umbilical vein endothelial cells (HUVECs) as well as the alignment, cardiac-specific proteins, and maturity-related gene expression of hiPSC-CMs on the aligned-nanofiber/microridge (AN-MR) substrate were studied. Compared with the glass slide and the single-aligned nanofiber substrate, the AN-MR substrate enhanced the proliferation, alignment, and cell−cell interaction of HUVECs and improved the length of the sarcomere and maturation-related gene expression of hiPSC-CMs. Finally, the response of hiPSC-CMs on different substrates to two typical cardiac drugs (isoproterenol and E-4031) was tested and analyzed, showing that the hiPSC-CMs on AN-MR substrates were more resistant to drugs than those in other groups, which was related to the higher maturity of the cells. Overall, the proposed micro-/nanohierarchical substrate supports the in vitro endothelium formation and enhances the maturation of hiPSC-CMs, which show great potential to be applied in the construction of in vitro models and tissue engineering.

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“…These studies also revealed that sensory nerves may tune down sympathetic nerve activity [ 16 , 62 , 105 ]. Sympathetic neurons release norepinephrine [ 70 , 123 ], which has been shown to strongly induce tumorigenesis [ 1 , 60 , 154 ]. It remains open the important question whether the effect of sensory innervations in the tumor microenvironment depend also on the modulation of the sympathetic tone.…”

Section: Discussionmentioning

confidence: 99%

Chemogenetic modulation of sensory neurons reveals their regulating role in melanoma progression

Costa

Silva

Prazeres

et al. 2021

acta neuropathol commun

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Sensory neurons have recently emerged as components of the tumor microenvironment. Nevertheless, whether sensory neuronal activity is important for tumor progression remains unknown. Here we used Designer Receptors Exclusively Activated by a Designer Drug (DREADD) technology to inhibit or activate sensory neurons’ firing within the melanoma tumor. Melanoma growth and angiogenesis were accelerated following inhibition of sensory neurons’ activity and were reduced following overstimulation of these neurons. Sensory neuron-specific overactivation also induced a boost in the immune surveillance by increasing tumor-infiltrating anti-tumor lymphocytes, while reducing immune-suppressor cells. In humans, a retrospective in silico analysis of melanoma biopsies revealed that increased expression of sensory neurons-related genes within melanoma was associated with improved survival. These findings suggest that sensory innervations regulate melanoma progression, indicating that manipulation of sensory neurons’ activity may provide a valuable tool to improve melanoma patients’ outcomes.

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

Cited by 11 publications

References 62 publications

Non-canonical role of the sympathetic nervous system in the day–night rhythm in heart rate

Non-canonical role of the sympathetic nervous system in the day–night rhythm in heart rate

Aligned Nanofibrous Net Deposited Perpendicularly on Microridges Supports Endothelium Formation and Promotes the Structural Maturation of hiPSC-Derived Cardiomyocytes

Chemogenetic modulation of sensory neurons reveals their regulating role in melanoma progression

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