Developmental Programming of Ischemic-Sensitive Phenotype in the Heart

描述(申请人提供)：心脏病是美国的主要死亡原因，缺血性心脏病是发病率和死亡率的主要原因。然而，分子机制在很大程度上仍然难以捉摸。除了其他危险因素外，大型流行病学和动物研究已经表明，发育过程中的胎儿压力与成年后缺血性心脏病风险的增加明显相关。糖皮质激素在应激反应中起着中心作用。我们最近的研究表明，母体/胎儿缺氧导致胎儿心脏糖皮质激素受体(GR)mRNA和蛋白丰度下降，并持续到成年后代，这表明在发育中的心脏中，GR基因的抑制存在于子宫表观遗传程序中。糖皮质激素在人和动物急性心肌缺血和再灌注损伤中的心脏保护作用的研究结果突显了心脏GR表达水平下降的病理生理学意义。我们的初步研究表明，缺氧增加了胎儿心脏GR基因启动子的甲基化。DNA甲基化是基因表达模式表观遗传修饰的主要机制。虽然GR启动子的甲基化已被报道为下丘脑-垂体-肾上腺轴的生理调节功能，但对GR基因在发育心脏中的表达模式及其功能影响的表观遗传调控知之甚少。这些拟议的研究将解决我们知识中的这些主要差距，并检验以下假设：在发育中的心脏中，糖皮质激素受体基因的表观遗传抑制会导致心脏对缺血敏感的表型的发育编程。我们提出了三个特定的目标来确定：1)妊娠期母体/胎儿缺氧增加了GR基因启动子甲基化导致发育心脏GR基因抑制，2)缺氧直接导致GR启动子甲基化和基因抑制升高，3)发育心脏缺氧介导的GR基因抑制有助于心脏对缺血敏感表型的发育编程。这些研究的总体影响是，这些发现不仅将显著提高我们对胎儿应激诱导心脏缺血敏感表型编程的分子机制的了解，从而提高我们对缺血性心脏病病理生理学的理解，而且它们还将为在健康和疾病的广泛发育编程领域中调节GR基因表达模式的表观遗传学机制提供重要的原创性见解，因为糖皮质激素在应激反应中起着共同和核心的作用。

DESCRIPTION (provided by applicant): Heart disease is the leading cause of death in the United States, with ischemic heart disease a major cause of morbidity and mortality. Yet the molecular mechanisms remain largely elusive. In addition to other risk factors, large epidemiological and animal studies have shown a clear association of fetal stress during the development with increased risk of ischemic heart disease in adulthood. Glucocorticoids play a center role in the response to stress. Our recent studies demonstrated that maternal/fetal hypoxia resulted in a decrease in glucocorticoid receptor (GR) mRNA and protein abundance in fetal hearts that persisted in adult offspring, suggesting in utero epigenetic programming of GR gene repression in the developing heart. The pathophysiological significance of decreased GR expression levels in the heart is highlighted by the findings that demonstrate cardioprotective effects of glucocorticoids in the acute setting of myocardial ischemia and reperfusion injury both in humans and in animals. Our preliminary studies suggested that hypoxia increased GR gene promoter methylation in fetal hearts. DNA methylation is a chief mechanism in epigenetic modification of gene expression patterns. Although methylation of the GR promoter has been reported to occur as function of physiological regulation of the hypothalamic- pituitary-adrenal axis, little is known about the epigenetic regulation of GR gene expression patterns in the developing heart and its functional consequences. The proposed studies will address these major gaps in our knowledge and test the hypothesis that epigenetic repression of glucocorticoid receptor gene in the developing heart results in developmental programming of ischemic-sensitive phenotype in the heart. Three specific aims are proposed to determine whether: 1) maternal/fetal hypoxia during gestation increases the promoter methylation resulting in GR gene repression in the developing heart, 2) hypoxia has direct causal effects leading to heightened GR promoter methylation and gene repression, and 3) hypoxia-mediated GR gene repression in the developing heart contributes to developmental programming of ischemic-sensitive phenotype in the heart. The overall impact of the proposed studies is that the findings will not only significantly advance our knowledge of molecular mechanisms underlying fetal stress-induced programming of ischemic-sensitive phenotype in the heart and hence improve our understanding of pathophysiology of ischemic heart disease, but they will also provide important original insights into epigenetic mechanisms regulating GR gene expression patterns in a broad field of developmental programming of health and disease, given that glucocorticoids play a common and center role in the stress response.