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Epigenetic down-regulation of BKCa channel by miR-181a contributes to the fetal and neonatal nicotine-mediated exaggerated coronary vascular tone in adult life.

ABSTRACT: BACKGROUND:Fetal origin of adult cardiovascular disease is one of the most pressing public concerns and economic problem in modern life. Maternal cigarette smoking/nicotine abuse increases the risk of cardiovascular disease in offspring. However, the underlying mechanisms and theranostics remain unclear. We hypothesized that fetal and neonatal nicotine exposure enhances microRNA-181a (miR-181a) which targets large-conductance Ca2+-activated K+ (BKCa) channels, resulting in increased coronary vascular tone in adult offspring. METHODS:Nicotine or saline was administered to pregnant rats via subcutaneous osmotic minipumps from gestational day 4 until postnatal day 10. Experiments were conducted in adult (~6?month old) male offspring. RESULTS:Nicotine enhanced pressure-induced coronary vascular tone, which was abrogated by BKCa channel blocker. Nicotine selectively attenuated coronary BKCa ?1 but not ? subunit expression. Functionally, nicotine suppressed BKCa current density and inhibited BKCa activator NS1619-induced coronary relaxations. Furthermore, activation of BKCa increased coronary flow and improved heart ischemia/reperfusion-induced infarction. Nicotine selectively enhanced miR-181a expression. MiR-181a mimic inhibited BKCa ?1 expression/channel current and decreased NS1619-induced coronary relaxation. Antioxidant eliminated the difference of BKCa current density between the saline and nicotine-treated groups and partially restored NS1619-induced relaxation in nicotine group. MiR-181a antisense decreased vascular tone and eliminated the differences between nicotine exposed and control groups. CONCLUSION:Fetal and neonatal nicotine exposure-mediated miR-181a overexpression plays an important role in nicotine-enhanced coronary vascular tone via epigenetic down-regulation of BKca channel mechanism, which provides a potentially novel therapeutic molecular target of miR-181a/BKca channels for the treatment of coronary heart ischemic disease.

SUBMITTER: Liu B

PROVIDER: S-EPMC6392075 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Epigenetic down-regulation of BK<sub>Ca</sub> channel by miR-181a contributes to the fetal and neonatal nicotine-mediated exaggerated coronary vascular tone in adult life.

Liu Bailin B Hu Xiangqun X Li Yong Y Ke Jun J Dasgupta Chiranjib C Huang Xiaohui X Walayat Andrew A Zhang Lubo L Xiao Daliao D

International journal of cardiology 20190131

<h4>Background</h4>Fetal origin of adult cardiovascular disease is one of the most pressing public concerns and economic problem in modern life. Maternal cigarette smoking/nicotine abuse increases the risk of cardiovascular disease in offspring. However, the underlying mechanisms and theranostics remain unclear. We hypothesized that fetal and neonatal nicotine exposure enhances microRNA-181a (miR-181a) which targets large-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> (BK<sub>Ca</sub>) chan ...[more]

PMID: 30738609

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Project description:Mammalian circadian (24 h) rhythms are timed by the pattern of spontaneous action potential firing in the suprachiasmatic nucleus (SCN). This oscillation in firing is produced through circadian regulation of several membrane currents, including large-conductance Ca2+- and voltage-activated K+ (BK) and L-type Ca2+ channel (LTCC) currents. During the day steady-state BK currents depend mostly on LTCCs for activation, whereas at night they depend predominantly on ryanodine receptors (RyRs). However, the contribution of these Ca2+ channels to BK channel activation during action potential firing has not been thoroughly investigated. In this study, we used a pharmacological approach to determine that both LTCCs and RyRs contribute to the baseline membrane potential of SCN action potential waveforms, as well as action potential-evoked BK current, during the day and night, respectively. Since the baseline membrane potential is a major determinant of circadian firing rate, we focused on the LTCCs contributing to low voltage activation of BK channels during the subthreshold phase. For these experiments, two LTCC subtypes found in SCN (CaV1.2 and CaV1.3) were coexpressed with BK channels in heterologous cells, where their differential contributions could be separately measured. CaV1.3 channels produced currents that were shifted to more hyperpolarized potentials compared with CaV1.2, resulting in increased subthreshold Ca2+ and BK currents during an action potential command. These results show that although multiple Ca2+ sources in SCN can contribute to the activation of BK current during an action potential, specific BK-CaV1.3 partnerships may optimize the subthreshold BK current activation that is critical for firing rate regulation.NEW & NOTEWORTHY BK K+ channels are important regulators of firing. Although Ca2+ channels are required for their activation in excitable cells, it is not well understood how BK channels activate using these Ca2+ sources during an action potential. This study demonstrates the differences in BK current activated by CaV1.2 and CaV1.3 channels in clock neurons and heterologous cells. The results define how specific ion channel partnerships can be engaged during distinct phases of the action potential.

Dataset Information

Epigenetic down-regulation of BKCa channel by miR-181a contributes to the fetal and neonatal nicotine-mediated exaggerated coronary vascular tone in adult life.

Publications

Epigenetic down-regulation of BK<sub>Ca</sub> channel by miR-181a contributes to the fetal and neonatal nicotine-mediated exaggerated coronary vascular tone in adult life.

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