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

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 ß1 but not α 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 ß1 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.