Various Regulatory Modes for Circadian Rhythmicity and Sexual Dimorphism in the Non-Neuronal Cardiac Cholinergic System

  • Shino Oikawa
  • Yuko Kai
  • Asuka Mano
  • Hisayuki Ohata
  • Takahiro Nemoto
  • Yoshihiko KakinumaEmail author
Original Article


Cardiomyocytes possess a non-neuronal cardiac cholinergic system (NNCCS) regulated by a positive feedback system; however, its other regulatory mechanisms remain to be elucidated, which include the epigenetic control or regulation by the female sex steroid, estrogen. Here, the NNCCS was shown to possess a circadian rhythm; its activity was upregulated in the light-off phase via histone acetyltransferase (HAT) activity and downregulated in the light-on phase. Disrupting the circadian rhythm altered the physiological choline acetyltransferase (ChAT) expression pattern. The NNCCS circadian rhythm may be regulated by miR-345, independently of HAT, causing decreased cardiac ChAT expression. Murine cardiac ChAT expression and ACh contents were increased more in female hearts than in male hearts. This upregulation was downregulated by treatment with the estrogen receptor antagonist tamoxifen, and in contrast, estrogen reciprocally regulated cardiac miR-345 expression. These results suggest that the NNCCS is regulated by the circadian rhythm and is affected by sexual dimorphism.


Acetylcholine Non-neuronal cardiac cholinergic system Circadian rhythm miRNA Sexual dimorphism 



This manuscript has been checked for language and edited by Cactus Communications Inc., Tokyo, Japan.

Compliance with Ethical Standards

The present study was approved by the ethical committee of Nippon Medical School (permission number 27-0003), and all procedures were performed in strict accordance with the recommendations set forth in the guidelines of the institution, Physiological Society of Japan and the ARRIVE guidelines.

Sources of Funding

The current study was supported mainly by the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (JSPS KAKENHI) (C) Grant Numbers 25460333 and 16K08560, and partly by the Smoking Research Foundation.

Conflict of Interest

The authors declare that they have no conflict of interest.

Human Subjects

No human studies were carried out by the authors for this article.


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of PhysiologyNippon Medical School Graduate School of MedicineTokyoJapan

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