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

> **NIH NIH R01** · EAST CAROLINA UNIVERSITY · 2020 · $385,314

## Abstract

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.

## Key facts

- **NIH application ID:** 9986575
- **Project number:** 5R01AA014441-13
- **Recipient organization:** EAST CAROLINA UNIVERSITY
- **Principal Investigator:** ABDEL A ABDEL-RAHMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,314
- **Award type:** 5
- **Project period:** 2004-05-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986575

## Citation

> US National Institutes of Health, RePORTER application 9986575, Sex/estrogen-dependent vulnerability to alcohol-evoked cardiotoxicity: Role of circadian rhythm regulated enzymes (5R01AA014441-13). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9986575. Licensed CC0.

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