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

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)依赖对酒精引起的心脏毒性的脆弱性。这种被忽视的翻译研究是及时的。 因为年轻女性的饮酒量正在迅速增加，尽管她们对 酒精的心脏毒性作用，与男性相比。虽然有限(主要发生在非心血管组织) 数据支持我们的科学假设，目前还没有关于心脏中是否存在雌二醇环心律相互作用的研究 或自主神经核通过心脏特异的miRNAs调节心脏氧化还原酶和功能，特别是在 酒精的存在。我们假设乙醇破坏了雌激素受体(ER)对雌激素受体(ER)的调节 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 促炎激素。具体地说，我们将阐明依赖ERα-per2的未解决的角色 心肌过氧化氢酶和乙醛脱氢酶(ALDH2)的差异上调和ALDH2的下调 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 心脏特异的miRNAs，调节保护或损伤。值得注意的是，过氧化氢酶和ALDH2调节细胞 乙醇的氧化还原状态和细胞存活以及氧化代谢。为了测试我们的新假设，我们 组建了一支有能力的研究团队，以执行包含 心血管、遗传学、细胞学和药理学研究。这些研究将对这一角色产生新的见解 E_2依赖的心脏保护和乙醇诱导的心脏毒性的昼夜节律以及识别 减轻女性由酒精引起的慢性心血管异常的新疗法。 本项目中要调查的两个逻辑上重叠的领域是： 目的1研究将验证这样一种假设，即干扰E2/ERα-per2氧化还原酶和心脏的循环调节 特异性miRNAs介导乙醇诱导的女性心肌氧化应激/功能障碍。中国的多层次研究 对乙醇诱发的心肌功能障碍敏感或耐药的大鼠模型，以及遗传模型(ERα/ ERβ/GPER KO和PER2功能丧失，mPer2，老鼠)将产生强有力的数据来验证我们的假设。 目的2项研究将验证酒精引起的心脏BH4耗竭/eNOS解偶联的假说 而E2/PER2对HO-1和过氧化氢酶的不同调节触发了死亡相关蛋白激酶-3(DAPK-3) 信号级联导致心肌氧化应激/功能障碍。我们还将确定细胞信号级联 作为缓解E2/昼夜节律依赖性心血管紊乱的新治疗靶点 由慢性酒精引起的女性。

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.