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: 10223099
• 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/10223099
• 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，我们试图了解中枢和心脏昼夜节律在性/雌激素中的作用 (E2) 依赖性的酒精引起的心脏毒性脆弱性这项被忽视的转化研究是及时的。 因为年轻女性的饮酒量正在迅速增加，尽管她们对酒精的敏感性更高 与男性相比，酒精的心脏毒性作用虽然有限（主要在非心血管组织中产生）。 数据支持我们的科学前提，目前还没有关于 E2-昼夜节律在心脏中是否相互作用的研究 或自主神经核通过心脏特异性 miRNA 调节心脏氧化还原酶和功能，特别是在 我们研究了乙醇对 E2/雌激素受体 (ER) 调节的破坏。 昼夜节律（PERIOD 基因；Per1/Per2）调节的氧化还原酶矛盾地将 E2 转化为 具体来说，我们将阐明 ERα-Per2 依赖性的未解决的作用。 心脏过氧化氢酶和乙醛脱氢酶 (ALDH2) 的不同上调，以及 血红素加氧酶（HO-1），在这个与女性健康相关的问题中，我们将重点关注这些心肌酶，以及 介导保护或损伤的心脏特异性 miRNA 值得注意的是，过氧化氢酶和 ALDH2 调节细胞。 为了检验我们的新假设，我们研究了氧化还原状态和细胞存活以及乙醇的氧化代谢。 组建一支有能力的研究团队，执行包括综合性在内的多维方法 这些研究将为心血管、遗传、细胞和药理学研究带来新的见解。 E2 依赖性心脏保护和乙醇诱导的心脏毒性中昼夜节律的影响以及识别 减轻女性酒精引起的慢性心血管异常的新疗法。 该项目要研究的两个逻辑上重叠的领域是： 目标 1 研究将检验以下假设：氧化还原酶和心脏的 E2/ERα-Per2 环调节被破坏 特定 miRNA 介导女性乙醇诱发的心肌氧化应激/功能障碍。 大鼠模型对乙醇引起的心肌功能障碍敏感或耐药，并且在遗传模型中（ERα/ ERβ/GPER KO 和 Per2 功能丧失（mPer2，小鼠）将生成可靠的数据来检验我们的假设。 目标 2 研究将检验以下假设：乙醇引起的心脏 BH4 耗竭/eNOS 解偶联 和 E2/Per2 对 HO-1 和过氧化氢酶的不同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。 作为减轻 E2/昼夜节律依赖性心血管紊乱的新治疗靶点 女性长期饮酒所致。