Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
Int J Cardiol. 2019 Apr 15;281:82-89. doi: 10.1016/j.ijcard.2019.01.099. Epub 2019 Jan 31.
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.
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.
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.
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.
胎儿期起源的成人心血管疾病是现代生活中最紧迫的公众关注和经济问题之一。母体吸烟/尼古丁滥用会增加后代患心血管疾病的风险。然而，其潜在机制和治疗方法仍不清楚。我们假设胎儿和新生儿尼古丁暴露会增强 microRNA-181a（miR-181a），其靶向大电导钙激活钾（BK）通道，导致成年后代冠状动脉血管张力增加。
尼古丁或生理盐水通过皮下渗透微型泵从妊娠第 4 天至出生后第 10 天给予孕鼠。在成年（约 6 个月大）雄性后代中进行实验。
尼古丁增强了压力诱导的冠状动脉血管张力，而 BK 通道阻滞剂则消除了这种作用。尼古丁选择性地减弱了冠状动脉 BKβ1，但不减弱 BKα亚基的表达。功能上，尼古丁抑制了 BK 电流密度，并抑制了 BK 激活剂 NS1619 引起的冠状动脉舒张。此外，BK 的激活增加了冠状动脉流量并改善了心脏缺血/再灌注引起的梗塞。尼古丁选择性地增强了 miR-181a 的表达。miR-181a 模拟物抑制了 BKβ1 的表达/通道电流，并减少了 NS1619 引起的冠状动脉舒张。抗氧化剂消除了盐水和尼古丁处理组之间 BK 电流密度的差异，并部分恢复了尼古丁组中 NS1619 诱导的舒张。miR-181a 反义寡核苷酸降低了血管张力，并消除了尼古丁暴露组和对照组之间的差异。
胎儿和新生儿尼古丁暴露介导的 miR-181a 过表达通过表观遗传下调 BK 通道机制在尼古丁增强冠状动脉血管张力中发挥重要作用，这为 miR-181a/BK 通道治疗冠心病提供了一个潜在的新的治疗分子靶点。
