Abstract
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.
Similar content being viewed by others
Change history
22 June 2017
An erratum to this article has been published.
References
Kakinuma, Y., Akiyama, T., & Sato, T. (2009). Cholinoceptive and cholinergic properties of cardiomyocytes involving an amplification mechanism for vagal efferent effects in sparsely innervated ventricular myocardium. The FEBS Journal, 276, 5111–5125.
Rana, O. R., Schauerte, P., Kluttig, R., Schröder, J. W., Koenen, R. R., Weber, C., Nolte, K. W., Weis, J., Hoffmann, R., Marx, N., & Saygili, E. (2010). Acetylcholine as an age-dependent non-neuronal source in the heart. Autonomic Neuroscience, 156, 82–89.
Rocha-Resende, C., Roy, A., Resende, R., Ladeira, M. S., Lara, A., de Morais Gomes, E. R., Prado, V. F., Gros, R., Guatimosim, C., Prado, M. A., & Guatimosim, S. (2012). Non-neuronal cholinergic machinery present in cardiomyocytes offsets hypertrophic signals. Journal of Molecular and Cellular Cardiology, 53, 206–216.
Roy, A., Fields, W. C., Rocha-Resende, C., Resende, R. R., Guatimosim, S., Prado, V. F., Gros, R., & Prado, M. A. (2013). Cardiomyocyte-secreted acetylcholine is required for maintenance of homeostasis in the heart. The FASEB Journal, 27, 5072–5082.
Kakinuma, Y., Akiyama, T., Okazaki, K., Arikawa, M., Noguchi, T., & Sato, T. (2012). A non-neuronal cardiac cholinergic system plays a protective role in myocardium salvage during ischemic insults. PloS One, 7, e50761.
Roy, A., Dakroub, M., Tezini, G. C., Liu, Y., Guatimosim, S., Feng, Q., Salgado, H. C., Prado, V. F., Prado, M. A., & Gros, R. (2016). Cardiac acetylcholine inhibits ventricular remodeling and dysfunction under pathologic conditions. The FASEB Journal, 30, 688–701.
Kakinuma, Y., Tsuda, M., Okazaki, K., Akiyama, T., Arikawa, M., Noguchi, T., & Sato, T. (2013). Heart-specific overexpression of choline acetyltransferase gene protects murine heart against ischemia through hypoxia-inducible factor-1α-related defense mechanisms. Journal of the American Heart Association, 2, e004887.
Oikawa, S., Iketani, M., & Kakinuma, Y. (2014). A non-neuronal cholinergic system regulates cellular ATP levels to maintain cell viability. Cellular Physiology and Biochemistry, 34, 781–789.
Kakinuma, Y., Furihata, M., Akiyama, T., Arikawa, M., Handa, T., Katare, R. G., & Sato, T. (2010). Donepezil, an acetylcholinesterase inhibitor against Alzheimer’s dementia, promotes angiogenesis in an ischemic hindlimb model. Journal of Molecular and Cellular Cardiology, 48, 680–693.
Kakinuma, Y., Ando, M., Kuwabara, M., Katare, R. G., Okudela, K., Kobayashi, M., & Sato, T. (2005). Acetylcholine from vagal stimulation protects cardiomyocytes against ischemia and hypoxia involving additive non-hypoxic induction of HIF-1alpha. FEBS Letters, 579, 2111–2118.
Chatterjee, N. A., & Singh, J. P. (2015). Novel interventional therapies to modulate the autonomic tone in heart failure. JACC Heart Fail, 3, 786–802.
Grassi, G., Bombelli, M., Seravalle, G., Dell'Oro, R., & Quarti-Trevano, F. (2010). Diurnal blood pressure variation and sympathetic activity. Hypertension Research, 33, 381–385.
Takeda, N., & Maemura, K. (2015). The role of clock genes and circadian rhythm in the development of cardiovascular diseases. Cellular and Molecular Life Sciences, 72, 3225–3234.
Blenck, C. L., Harvey, P. A., Reckelhoff, J. F., & Leinwand, L. A. (2016). The importance of biological sex and estrogen in rodent models of cardiovascular health and disease. Circulation Research, 118, 1294–1312.
Oikawa, S., Mano, A., Takahashi, R., & Kakinuma, Y. (2015). Remote ischemic preconditioning with a specialized protocol activates the non-neuronal cardiac cholinergic system and increases ATP content in the heart. International Immunopharmacology, 29, 181–184.
Oikawa, S., Kai, Y., Tsuda, M., Ohata, H., Mano, A., Mizoguchi, N., Sugama, S., Nemoto, T., Suzuki, K., Kurabayashi, A., Muramoto, K., Kaneda, M., & Kakinuma, Y. (2016). Non-neuronal cardiac cholinergic system influences CNS via the vagus nerve to acquire a stress-refractory propensity. Clinical Science (London, England), 130, 1913–1928.
Girod, R., Popov, S., Alder, J., Zheng, J. Q., Lohof, A., & Poo, M. M. (1995). Spontaneous quantal transmitter secretion from myocytes and fibroblasts: comparison with neuronal secretion. The Journal of Neuroscience, 15, 2826–2838.
Murakami, N., Takahashi, K., & Kawashima, K. (1984). Effect of light on the acetylcholine concentrations of the suprachiasmatic nucleus in the rat. Brain Research, 311, 358–360.
Muller, J. E., & Tofler, G. H. (1991). Circadian variation and cardiovascular disease. The New England Journal of Medicine, 325, 1038–1039.
Muller, J. E., Tofler, G. H., & Stone, P. H. (1989). Circadian variation and triggers of onset of acute cardiovascular disease. Circulation, 79, 733–743.
Hut, R. A., & Van der Zee, E. A. (2011). The cholinergic system, circadian rhythmicity, and time memory. Behavioural Brain Research, 221, 466–480.
Srivastava, S. K., Bhardwaj, A., Arora, S., Tyagi, N., Singh, S., Andrews, J., McClellan, S., Wang, B., & Singh, A. P. (2015). MicroRNA-345 induces apoptosis in pancreatic cancer cells through potentiation of caspase-dependent and -independent pathways. British Journal of Cancer, 113, 660–668.
Schou, J. V., Rossi, S., Jensen, B. V., Nielsen, D. L., Pfeiffer, P., Høgdall, E., Yilmaz, M., Tejpar, S., Delorenzi, M., Kruhøffer, M., & Johansen, J. S. (2014). miR-345 in metastatic colorectal cancer: a non-invasive biomarker for clinical outcome in non-KRAS mutant patients treated with 3rd line cetuximab and irinotecan. PloS One, 9, e99886.
Chen, Q. G., Zhou, W., Han, T., Du, S. Q., Li, Z. H., Zhang, Z., Shan, G. Y., & Kong, C. Z. (2016). MiR-345 suppresses proliferation, migration and invasion by targeting Smad1 in human prostate cancer. Journal of Cancer Research and Clinical Oncology, 142, 213–224.
Doi, M., Hirayama, J., & Sassone-Corsi, P. (2006). Circadian regulator CLOCK is a histone acetyltransferase. Cell, 125, 497–508.
Hirayama, J., Sahar, S., Grimaldi, B., Tamaru, T., Takamatsu, K., Nakahata, Y., & Sassone-Corsi, P. (2007). CLOCK-mediated acetylation of BMAL1 controls circadian function. Nature, 450, 1086–1090.
Du, X. J., Dart, A. M., & Riemersma, R. A. (1994). Sex differences in the parasympathetic nerve control of rat heart. Clinical and Experimental Pharmacology & Physiology, 21, 485–493.
Aronson, D., & Burger, A. J. (2000). Gender-related differences in modulation of heart rate in patients with congestive heart failure. Journal of Cardiovascular Electrophysiology, 11, 1071–1077.
Calovini, T., Haase, H., & Morano, I. (1995). Steroid-hormone regulation of myosin subunit expression in smooth and cardiac muscle. Journal of Cellular Biochemistry, 59, 69–78.
Schaible, T. F., Malhotra, A., Ciambrone, G., & Scheuer, J. (1984). The effects of gonadectomy on left ventricular function and cardiac contractile proteins in male and female rats. Circulation Research, 54, 38–49.
Yan, L., Ge, H., Li, H., Lieber, S. C., Natividad, F., Resuello, R. R., Kim, S. J., Akeju, S., Sun, A., Loo, K., Peppas, A. P., Rossi, F., Lewandowski, E. D., Thomas, A. P., Vatner, S. F., & Vatner, D. E. (2004). Gender-specific proteomic alterations in glycolytic and mitochondrial pathways in aging monkey hearts. Journal of Molecular and Cellular Cardiology, 37, 921–929.
Nordström, P., Religa, D., Wimo, A., Winblad, B., & Eriksdotter, M. (2013). The use of cholinesterase inhibitors and the risk of myocardial infarction and death: a nationwide cohort study in subjects with Alzheimer’s disease. European Heart Journal, 34, 2585–2591.
Sato, K., Urbano, R., Yu, C., Yamasaki, F., Sato, T., Jordan, J., Robertson, D., & Diedrich, A. (2010). The effect of donepezil treatment on cardiovascular mortality. Clinical Pharmacology and Therapeutics, 88, 335–338.
Wu, P. H., Lin, Y. T., Hsu, P. C., Yang, Y. H., Lin, T. H., & Huang, C. T. (2015). Impact of acetylcholinesterase inhibitors on the occurrence of acute coronary syndrome in patients with dementia. Scientific Reports, 5, 15451.
Acknowledgements
This manuscript has been checked for language and edited by Cactus Communications Inc., Tokyo, Japan.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
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.
Additional information
Associate Editor Saptarsi Haldar oversaw the review of this article
An erratum to this article is available at https://doi.org/10.1007/s12265-017-9760-2.
Rights and permissions
About this article
Cite this article
Oikawa, S., Kai, Y., Mano, A. et al. Various Regulatory Modes for Circadian Rhythmicity and Sexual Dimorphism in the Non-Neuronal Cardiac Cholinergic System. J. of Cardiovasc. Trans. Res. 10, 411–422 (2017). https://doi.org/10.1007/s12265-017-9750-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12265-017-9750-4