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 Ca-activated K (BK) 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 BK channel blocker. Nicotine selectively attenuated coronary BK β1 but not α subunit expression. Functionally, nicotine suppressed BK current density and inhibited BK activator NS1619-induced coronary relaxations. Furthermore, activation of BK increased coronary flow and improved heart ischemia/reperfusion-induced infarction. Nicotine selectively enhanced miR-181a expression. MiR-181a mimic inhibited BK β1 expression/channel current and decreased NS1619-induced coronary relaxation. Antioxidant eliminated the difference of BK 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 BK channel mechanism, which provides a potentially novel therapeutic molecular target of miR-181a/BK channels for the treatment of coronary heart ischemic disease.
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| http://dx.doi.org/10.1016/j.ijcard.2019.01.099 | DOI Listing |
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