Department of Physiology, Nippon Medical School Graduate School of Medicine, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan.
J Cardiovasc Transl Res. 2017 Aug;10(4):411-422. doi: 10.1007/s12265-017-9750-4. Epub 2017 May 11.
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.
心肌细胞具有受正反馈系统调控的非神经型心脏胆碱能系统（NNCCS）；然而，其其他调控机制仍有待阐明，包括表观遗传调控或女性性激素雌激素的调控。在这里，NNCCS 被证明具有昼夜节律；其活性在光关闭阶段通过组蛋白乙酰转移酶（HAT）活性上调，在光开启阶段下调。破坏昼夜节律会改变生理胆碱乙酰转移酶（ChAT）的表达模式。NNCCS 的昼夜节律可能受 miR-345 调控，不依赖于 HAT，导致心脏 ChAT 表达减少。与雄性心脏相比，雌性心脏的鼠类心脏 ChAT 表达和 ACh 含量增加更多。这种上调被雌激素受体拮抗剂他莫昔芬处理下调，相反，雌激素反过来调节心脏 miR-345 的表达。这些结果表明，NNCCS 受昼夜节律调控，并受性别二态性影响。
