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

• 批准号: 9769595
• 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
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769595
• 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' 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

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，我们试图了解中央和心脏昼夜节律在性别/雌激素中的作用 （E2）依赖于酒精诱发的心脏毒性的脆弱性。这项被忽视的翻译研究是及时的 因为年轻妇女的饮酒迅速越来越高于她们对 与男性相比，酒精的心脏毒性作用。虽然有限（主要是在非心血管组织中产生的） 数据支持我们的科学前提，没有关于E2-Circardian节奏相互作用的研究 或自主核调节心脏氧化还原酶并通过心脏特异性miRNA功能，特别是在 存在酒精。我们假设E2/雌激素受体（ER）调节的乙醇破坏 昼夜节律（周期基因； PER1/PER2）调节的氧化还原酶矛盾地将E2转化为A 促炎马酮。特别是，我们将阐明ERα-PER2依赖性的未解决的作用 心脏过氧化氢酶和醛脱氢酶（ALDH2）的分歧上调，并下调 在这个与女性健康相关的问题中，血红素加仑酶（HO-1）。我们将专注于这些心脏酶，以及 介导保护或伤害的心脏特异性miRNA。值得注意的是，过氧化氢酶和ALDH2调节细胞 氧化还原状态和细胞存活以及乙醇的氧化代谢。为了检验我们的新假设，我们 组建了一个有能力的研究团队，以执行多维方法包括集成 心血管，遗传，细胞和药物研究。这些研究将对该角色产生新的见解 E2依赖性心脏保护和乙醇引起的心脏毒性的昼夜节律以及识别 减轻女性酒精引起的慢性心血管异常的新疗法。 在该项目中要研究的两个逻辑上的重叠领域是： AIM 1研究将检验以下假设：氧化还原酶和心脏E2/ERα-PER2环的破坏 特定的miRNA介导雌性中乙醇诱发的心肌氧化应激/功能障碍。多级研究 大鼠模型对乙醇诱发的心肌功能障碍敏感或抗性，在遗传模型中（ERα/ ERβ/GPER KO和PER2功能丧失，MPER2，小鼠）将产生强大的数据来检验我们的假设。 AIM 2研究将检验以下假设：伴随乙醇诱发的心脏BH4部署/ENOS解偶联 HO-1和过氧化氢酶的E2/PER2发散调节触发与死亡相关的蛋白激酶-3（DAPK-3） 信号传导级联导致心肌氧化应激/功能障碍。我们还将确定细胞信号级联 作为减轻E2/昼夜节律依赖性心血管进化的新型热目标 由女性中的慢性乙醇引起。