Fetal origins of cardiovascular disease is a major public health concern in modern life. Epidemiological studies have clearly shown an increased risk of cardiovascular disease in children born to women who smoked during pregnancy, and studies in differential animal models suggest that nicotine is one of the key factors contributing to the fetal programming of adult coronary heart ischemic disease. However, the epigenetic molecular mechanisms and potential therapeutic target for the fetal programming of heart ischemic disease remain largely unknown. Increasing evidence supports the pivotal role of microRNAs (miRNAs) in the setting of coronary heart ischemic disease and have emerged as promising therapeutic targets. As one of the pivotal epigenetic mechanisms, miRNAs are sensitive to various prenatal insults including maternal tobacco abuse, resulting in aberrant regulation of target gene expression in developing fetus. One of the target proteins for miRNAs is the large-conductance Ca -activated K (BKCa) channel in vasculatures. BKCa channel is 2+ + abundantly expressed in coronary arteries and plays a key role in regulating coronary vascular tone, coronary flow and heart function. Recent studies have shown that antenatal nicotine exposure increases the heart vulnerability to ischemic injury in adult offspring. Of importance, our preliminary data indicated that antenatal nicotine increased specific BKCa ?1-targeting miRNA (miR-181a) and decreased BKca ?1 subunit expression level of the coronary arteries in offspring. With these exciting findings and many highly novel leads, we are positioned to move the field forward significantly by testing the central hypothesis that therapeutic inhibition of the specific BKca channel-targeting miRNA reverses antenatal nicotine-mediated development of coronary heart ischemia-sensitive phenotype in offspring. To test this hypothesis, three specific aims are proposed in our well-established animal model of nicotine-treated pregnant rats and their offspring. Specific Aim 1 will determine whether treatment with specific miRNA (miR-181a) inhibitor restores antenatal nicotine-mediated BKCa channel repression by binding at 3' UTR of BKCa ?1 mRNA region in coronary arteries. Specific Aim 2 will determine whether therapeutic manipulation of the specific miRNA (miR-181a) rescues antenatal nicotine- mediated decreased BKCa channel activity and increased coronary vascular tone. Specific Aim 3 will determine whether therapeutic inhibition of specific BKca-targeting miRNA (LNA anti-miR-181a) rescues antenatal nicotine-mediated development of coronary heart ischemia-sensitivity phenotype. On the basis of outcomes and given the fact that miRNA antisense-based therapies have already entered clinical trials, this project will offer the real possibility that therapeutic manipulation of specific BKca-targeting miRNA could translate into clinical for prevention or treatment of the fetal origins of coronary heart ischemic disease and coronary heart disease in general.
NIH ExPorter
NIH ExPorter