The long-term goal of the project is to study the effect of prenatal hypoxia on fetal heart development and its lifelong pathophysiological consequences in the adult heart. Of all the stresses to which the fetus is subjected, perhaps the most important and clinically relevant is that of hypoxia. Human epidemiological studies have shown a clear association of adverse intrauterine environment and an increased risk of ischemic heart disease in adulthood. Recently, we have found that prenatal hypoxia increases apoptosis in the fetal heart and causes a gender-dependent increase in heart susceptibility to ischemia and reperfusion injury in adult male offspring. Among other mechanisms, numerous studies have demonstrated that PKCe plays a pivotal role of cardioprotection during ischemia and reperfusion injury. Our preliminary data showed that prenatal hypoxia decreased PKCe protein levels selectively in the heart of adult male offspring, suggesting an in utero, gender-specific programming of PKCe gene expression pattern in the heart. The proposed studies focus on the underlying mechanisms, and will test the main hypothesis that prenatal hypoxia causes a gender-specific increase in DMA methylation of the PKCe gene and a down-regulation of PKCe gene expression in the heart, resulting in an increased heart susceptibility to ischemia and reperfusion injury in adult male offspring. To test the hypothesis, 4 Specific Aims are designed, which will test whether prenatal hypoxia causes 1) a gender- specific increase in heart susceptibility to ischemia and reperfusion injury in adult offspring, 2) a gender-specific down-regulation of PKCe gene expression in the heart, 3) a gender-specific increase in DNA methylation of the PKCe gene in the heart, and 4) whether DNA methylation of the PKCe gene plays a key role in the prenatal hypoxic-induced, gender-specific increase in heart susceptibility to ischemia and reperfusion injury. To achieve these aims, we propose a series of experiments in a pregnant rat model, and will determine the effects of prenatal hypoxic exposure on DNA methylation of the PKCe gene, PKCe gene expression, and postischemic recovery of left ventricular function and myocardial infarct size in hearts of male and female fetuses, and male and female adult offspring. The results will provide exciting novel insights into molecular mechanisms of epigenetic programming in the gene expression pattern involved in the adverse effects of fetal chronic hypoxia on the heart development, and its lifelong pathophysiological consequences in the adult heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083966-05
Application #
8007434
Study Section
Special Emphasis Panel (ZRG1-EMNR-G (05))
Program Officer
Schramm, Charlene A
Project Start
2007-01-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2011
Total Cost
$362,250
Indirect Cost
Name
Loma Linda University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
009656273
City
Loma Linda
State
CA
Country
United States
Zip Code
92350
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Li, Yong; Ma, Qingyi; Halavi, Shina et al. (2016) Fetal stress-mediated hypomethylation increases the brain susceptibility to hypoxic-ischemic injury in neonatal rats. Exp Neurol 275 Pt 1:1-10
Song, Minwoo A; Paradis, Alexandra N; Gay, Maresha S et al. (2015) Differential expression of microRNAs in ischemic heart disease. Drug Discov Today 20:223-35
Martinez, Shannalee R; Gay, Maresha S; Zhang, Lubo (2015) Epigenetic mechanisms in heart development and disease. Drug Discov Today 20:799-811
Ma, Qingyi; Zhang, Lubo (2015) Epigenetic programming of hypoxic-ischemic encephalopathy in response to fetal hypoxia. Prog Neurobiol 124:28-48
Paradis, Alexandra; Xiao, Daliao; Zhou, Jianjun et al. (2014) Endothelin-1 promotes cardiomyocyte terminal differentiation in the developing heart via heightened DNA methylation. Int J Med Sci 11:373-80
Gonzalez-Rodriguez, Pablo J; Xiong, Fuxia; Li, Yong et al. (2014) Fetal hypoxia increases vulnerability of hypoxic-ischemic brain injury in neonatal rats: role of glucocorticoid receptors. Neurobiol Dis 65:172-9
Xiao, DaLiao; Huang, Xiaohui; Xue, Qin et al. (2014) Antenatal hypoxia induces programming of reduced arterial blood pressure response in female rat offspring: role of ovarian function. PLoS One 9:e98743
Ma, Qingyi; Xiong, Fuxia; Zhang, Lubo (2014) Gestational hypoxia and epigenetic programming of brain development disorders. Drug Discov Today 19:1883-96
Xue, Qin; Patterson, Andrew J; Xiao, Daliao et al. (2014) Glucocorticoid modulates angiotensin II receptor expression patterns and protects the heart from ischemia and reperfusion injury. PLoS One 9:e106827

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