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Sex/estrogen-dependent vulnerability to alcohol-evoked cardiotoxicity: Role of circadian rhythm regulated enzymes

性别/雌激素依赖性酒精诱发心脏毒性的脆弱性：昼夜节律调节酶的作用

基本信息

批准号：
10455478
负责人：
ABDEL A ABDEL-RAHMAN
金额：
$ 38.53万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10455478
关键词：
Address Adverse effects Alcohol consumption Alcohols Animal Model Area Award Cardiac Cardiotoxicity Cardiovascular system Cell Nucleus Cell Respiration Cell Survival Chronic Circadian Rhythms DAP kinase Data Dose Down-Regulation Environment Enzymes Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Ethanol Ethanol Metabolism Exhibits Female Functional disorder GPER gene Genes Genetic Genetic Models Heart Hormones Inflammatory Injury Intervention Knockout Mice Knowledge Mediating MicroRNAs Modeling Molecular Mus Myocardial Myocardial dysfunction NADPH Oxidase Oxidation-Reduction Oxidative Stress Pharmacology Study Physiological Play Prevention Rattus Regulation Research Resistance Role Signal Transduction Testing Time Tissues Translational Research Up-Regulation Woman Women&apos s Health alcohol effect aldehyde dehydrogenases cardioprotection cardiovascular health catalase chronic alcohol ingestion circadian pacemaker heart function heart preservation heme oxygenase-1 insight knock-down loss of function male men new therapeutic target novel novel therapeutics prevent sex tetrahydrobiopterin young woman

项目摘要

Here, we seek to understand the role of central and cardiac circadian rhythm in the sex/estrogen (E2)-dependent vulnerability to alcohol-evoked cardiotoxicity. This overlooked translational research is timely because young women's alcohol consumption is rapidly increasing despite their higher sensitivity to the cardiotoxic effect of alcohol, compared to men. While limited (mostly generated in non-cardiovascular tissues) data support our scientific premise, there are no studies on whether E2-circardian rhythm interaction in the heart or autonomic nuclei regulates cardiac redox enzyme and function via heart specific miRNAs, particularly in the presence of alcohol. We hypothesize that ethanol disruption of the E2/estrogen receptor (ER) modulation of the circadian rhythm (PERIOD genes; Per1/Per2)-regulated redox enzymes paradoxically transforms E2 into a pro-inflammatory hormone. Specifically, we will elucidate the unresolved role of the ERα-Per2 dependent divergent upregulation of cardiac catalase and aldehyde dehydrogenase (ALDH2), and downregulation of hemeoxygenase (HO-1), in this female health related problem. We will focus on these cardiac enzymes, and heart-specific miRNAs that mediate protection or injury. Notably, catalase and ALDH2 regulate the cellular redox status and cell survival as well as oxidative metabolism of ethanol. To test our novel hypotheses, we assembled a capable research team to execute a multidimensional approach encompassing integrative cardiovascular, genetic, cellular and pharmacological studies. These studies will yield new insights into the role of the circadian rhythm in E2-dependent cardioprotection and ethanol-induced cardiotoxicity as well as identifying novel therapeutics for mitigating the chronic cardiovascular anomalies caused by alcohol in females. The two logically overlapping areas to be investigated in this project are: Aim 1 studies will test the hypothesis that disruption of the E2/ERα-Per2 loop regulation of redox enzymes and heart specific miRNAs mediate ethanol-evoked myocardial oxidative stress/dysfunction in females. Multilevel studies in rat models sensitive, or resistant, to ethanol-evoked myocardial dysfunction, and in genetic models (ERα/ ERβ/GPER KO and Per2 loss of function, mPer2, mice) will generate robust data to test our hypothesis. Aim 2 studies will test the hypothesis that concomitant ethanol-evoked cardiac BH4 depletion/eNOS uncoupling and E2/Per2 divergent regulation of HO-1 and catalase trigger the death associated protein kinase-3 (DAPK-3) signaling cascade to cause myocardial oxidative stress/dysfunction. We will also identify cell signaling cascades as novel therapeutic targets for alleviating the E2/circadian rhythm-dependent cardiovascular derangements caused by chronic ethanol in females.

在这里，我们试图了解中枢和心脏昼夜节律在性/雌激素调节中的作用。（E2）依赖性对酒精诱发的心脏毒性的脆弱性。这种被忽视的翻译研究是及时的因为年轻女性的酒精消费量正在迅速增加，尽管她们对酒精的敏感性更高。酒精对心脏的毒性作用，与男性相比。虽然有限（主要在非心血管组织中产生）数据支持我们的科学前提，没有关于心脏中E2-昼夜节律相互作用的研究或自主神经核通过心脏特异性miRNAs调节心脏氧化还原酶和功能，特别是在酒精的存在。我们假设，乙醇对E2/雌激素受体（ER）调节的破坏，昼夜节律（PERIOD基因; Per 1/Per 2）调节的氧化还原酶矛盾地将E2转化为一种促炎激素具体来说，我们将阐明ERα-Per 2依赖性的未解决的作用，心脏过氧化氢酶和醛脱氢酶（ALDH 2）的不同上调，血红素氧合酶（HO-1），在这个女性健康相关的问题。我们将重点关注这些心肌酶，心脏特异性miRNA介导保护或损伤。值得注意的是，过氧化氢酶和ALDH 2调节细胞内的氧化还原状态和细胞存活以及乙醇的氧化代谢。为了测试我们的新假设，我们组建了一个有能力的研究团队，执行一个多层面的方法，包括综合心血管、遗传、细胞和药理学研究。这些研究将产生新的见解的作用 E2依赖性心脏保护和乙醇诱导的心脏毒性的昼夜节律，以及识别用于减轻女性中由酒精引起的慢性心血管异常的新疗法。本项目将调查的两个逻辑上相互重叠的领域是：目的1研究将验证E2/ERα-Per 2环调节氧化还原酶和心脏的破坏的假设，特异性miRNA介导女性乙醇诱发的心肌氧化应激/功能障碍多层次研究对乙醇诱发的心肌功能障碍敏感或抵抗的大鼠模型，以及遗传模型（ERα/ ERβ/GPER KO和Per 2功能丧失，mPer 2，小鼠）将产生稳健的数据来检验我们的假设。目的2研究将检验伴随乙醇诱发的心脏BH 4耗竭/eNOS解偶联 HO-1和过氧化氢酶的E2/Per 2趋异调节触发死亡相关蛋白激酶-3（DAPK-3）信号级联导致心肌氧化应激/功能障碍。我们还将识别细胞信号级联作为缓解E2/昼夜节律依赖性心血管紊乱的新治疗靶点女性慢性酒精中毒