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Fetal nicotine exposure develops heart ischemia-sensitive phenotype

Institution: Loma Linda University
Investigator(s): DaLiao Xiao,
Award Cycle: 2019 (Cycle 29) Grant #: T29IR0437 Award: $1,185,000
Subject Area: Cardiovascular and Cerebrovascular Disease
Award Type: High Impact Research Project Award

Initial Award Abstract
Cigarette smoking during pregnancy is associated with numerous adverse outcomes for the developing fetus, as well as an increased risk of poor health in adulthood. Although the safety of nicotine use (nicotine gum or patch) during pregnancy has been evaluated in short-term human trials, the long-term effects of fetal nicotine exposure are uncertain. In addition, electronic cigarette (e-cigarette), an electronic nicotine delivery system has been introduced in the global market during the past ten years. Thus, nicotine addiction and nicotine abuse are becoming a potential health concern in the 21st century. Recent studies have shown that e-cigarettes can alter heart function and affect blood hematology, however, little direct work has been done on the health effects of e-cigarettes products on prenatal development or adult health. Therefore, study of the long-term consequences of fetal nicotine exposure either from tobacco smoking, NRT or e-cigarette has significant public health impact and clinic implications. Our recent studies have demonstrated that perinatal nicotine exposure increases heart ischemic injury and dysfunction in postnatal life. However, the molecular mechanisms remain unclear. In this project, we test the novel hypothesis that antenatal nicotine exposure enhances cardiac angiotensin II type 2 receptor (AT2R) gene expression through DNA methylation mechanism, leading to development of heart ischemia-sensitive phenotype in offspring. To test this hypothesis, we propose three specific aims in our well-established animal model of nicotine-treated pregnant rats and their offspring. Project outcomes are expected to provide new evidence that nicotine exposure during pregnancy could modify cardiac AT2R gene expression. This epigenetic change of AT2R gene by DNA methylation provides a potential mechanistic link between smoking/nicotine use by pregnant women and the development of cardiac ischemic disease in their offspring. Understanding the mechanism is of fundamental physiologic importance in its own right, as well as having considerable clinical relevance for improving cardiac function, and reducing nicotine-induced cardiovascular disease.