Sex/estrogen-dependent vulnerability to alcohol-evoked cardiotoxicity: Role of circadian rhythm regulated enzymes
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Overview
abstract
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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 important because women, compared to men, are more sensitive to alcohol-evoked cardiotoxicity, and there is a steady rise in alcohol consumption by young women in the US. While limited data on E2-circardian rhythm interaction (in non-cardiovascular tissues) support our scientific premise, there are no studies on a similar interaction in the heart or in cardiovascular nuclei and its regulation of cardiac redox enzymes, heart specific miRNAs, and cardiac function, 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 ER?-Per2 dependent divergent upregulation of cardiac catalase and aldehyde dehydrogenase (ALDH2), and downregulation of hemeoxygenase (HO-1), in this women's health related problem. We focus on these cardiac enzymes, and their interrelated heart-specific miRNAs, because they regulate the cellular redox status, cell survival and oxidative metabolism of ethanol (catalase and ALDH2). To test our novel hypotheses, we assembled a capable research team to execute a multidimensional approach that encompasses integrative cardiovascular, genetic, cellular and pharmacological studies. These studies will yield new insights into the role of the circadian rhythm in the E2-dependent cardioprotection and cardiotoxicity (when combined with ethanol) as well as identifying novel therapeutics for mitigating the chronic cardiovascular anomalies caused by alcohol in females.
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