# miRNA as a novel therapeutic target in antenatal nicotine-induced ischemic heart

> **NIH NIH R01** · LOMA LINDA UNIVERSITY · 2021 · $321,293

## Abstract

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 β1-targeting miRNA (miR-181a) and decreased BKca β1 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 β1 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...

## Key facts

- **NIH application ID:** 10151458
- **Project number:** 5R01HD088039-05
- **Recipient organization:** LOMA LINDA UNIVERSITY
- **Principal Investigator:** DALIAO XIAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $321,293
- **Award type:** 5
- **Project period:** 2017-07-12 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151458

## Citation

> US National Institutes of Health, RePORTER application 10151458, miRNA as a novel therapeutic target in antenatal nicotine-induced ischemic heart (5R01HD088039-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10151458. Licensed CC0.

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