# The impact of estrogen receptor alpha on cardiomyocellular metabolism and health

> **NIH NIH U54** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $385,875

## Abstract

Project 3: The impact of estrogen receptor alpha on cardiomyocellular metabolism and health
ABSTRACT Inactivating mutations and reductions in ESR1 (encodes ERα) are associated with
cardiometabolic disease risk in women and men. Moreover, the menopausal transition drives reduction of
cardiometabolic health and increased heart failure incidence. However, the causal mechanisms underlying
heart failure risk in women during this life phase, and the specific cell types impacted by impairment in
estrogen action are inadequately defined. Since aspects of cardiometabolic decline including insulin
resistance, obesity, and cardiac dysfunction are recapitulated in ERα null mice, our laboratory has
subsequently performed a tissue dissection approach to understand the cell-specific impact of ERα action
on metabolism and tissue function. In this proposal we focused specifically on the role of ERα on cardiac
function. A primary limitation regarding previous reports of estradiol action in cardiac tissue is the lack of
specificity in the manipulation of ERα in cardiomyocytes in vivo. To overcome this limitation, we are the
first laboratory to generate mice with a conditional cardiomyocellular-specific knockdown (hERαKD) or
overexpression (hERαOE) of Esr1. In Aim 1 of this proposal we will determine the impact of hERαKD on
mitochondrial metabolism, cardiac tissue integrity, and heart function. We hypothesize that
cardiomyocellular knockdown of Esr1 disrupts mitochondrial metabolism contributing to pathogenic shifts
in substrate metabolism, inflammation, fibrosis, and susceptibility to the damaging effects of cardiotoxic
agents (e.g. Doxorubicin). In Aim 2 we will determine the impact of conditional cardiomyocellular-specific
overexpression of Esr1, hERαOE, on mitochondrial metabolism, cardiac tissue integrity, and protection
against high fat diet feeding and cardiotoxic agents. Importantly, phenotypic outcomes in these mouse
models, integrated with findings in human subjects, will allow us to ascertain the ERα-regulated
transcriptome in heart and establish mechanisms of ERα control over novel target genes. The overarching
goal of our work is to determine the impact of impaired estrogen receptor action in the pathobiology of
heart failure and identify targets of therapeutic opportunity to protect women against cardiometabolic
disease.

## Key facts

- **NIH application ID:** 10919844
- **Project number:** 5U54HL170326-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Andrea L Hevener
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $385,875
- **Award type:** 5
- **Project period:** 2018-09-20 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10919844

## Citation

> US National Institutes of Health, RePORTER application 10919844, The impact of estrogen receptor alpha on cardiomyocellular metabolism and health (5U54HL170326-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10919844. Licensed CC0.

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