# Estrogen receptor and the cardiovascular system

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2021 · —

## Abstract

Project Summary/Abstract
Estrogen action has been shown in animal models and to an extent in humans to mitigate various forms of
cardiovascular disease, including hypertension, atherosclerosis, and ischemia/reperfusion injury. Estrogen acts
at its receptors, ERalpha and ERbeta. There is also strong data that estrogen prevents the development of
cardiac hypertrophy, fibrosis, and progression to heart failure, particularly in human-relevant animal models
when started early in the course of disease. These effects of estrogen are mainly through actions at the
ERbeta isoform, especially from the membrane-localized pool that stimulates signal transduction.
One potential target of ERbeta is the important transcription factor, KLF15 that is proposed to have anti-
hypertrophic properties. Using a relevant model for human disease, involving low dose Angiotensin II (Ang II)
infusion over 4 weeks in ovariectomized, wild type and ERbeta KO female mice will occur. The impact of AngII
and estradiol (E2) or an ERbeta-specific agonist, -LGND2, is used to determine effects on the expression of
this transcription factor in the left cardiac ventricle, postulating that membrane E2/ERbeta signaling restores
the expression of KLF15 that is reduced by AngII alone infusion. Male mice will also be investigated. Also, in-
vitro studies using cultured, freshly isolated neonatal rat cardiomyocytes will determine whether AngII reduces,
while E2 or BLGND restores nuclear localization of KLF15, and interaction with important hypertrophy-
controlling nuclear proteins such as myocardin, SRF, GATA-2 and MEF, and recruit epigenetic regulators
including HDACs 2 and 5, and p300. We propose this regulates important myocyte effector genes/protein
expression and myocyte function that will be determined. Whether nuclear ERcontributes will be determined
in 2 cell models of cell-selective ER pool loss.
An important cardiovascular protein and its myocyte cell membrane receptor, apelin and APJ respectively, are
known to mitigate the development of cardiac hypertrophy, fibrosis, and disease progression. It may be that
membrane ERbeta signaling and actions require this complex and activation of this system at the abundance
and functional levels. This will be determined in-vitro and in-vivo, the latter using ovariectomized, wild type,
ERbeta KO, and cardiomyocyte-specific APJ KO mice (Cre-Flox). This model will definitively implicate the role
of APJ in these cells for the action of E2/ERbeta to mitigate in-vivo AngII effects on blood pressure and cardiac
hypertrophy, fibrosis, and cardiac functional compromise. Male mice will also be used.
Two compelling issues in considering whether a proprietary ERbeta agonist could eventually be used in
humans are whether ERbeta activation 1) reverses established disease, and 2) whether this might be relevant
to male mammals. The 4 week model of AngII infusion +/- E2 or BLGND will be done in ovariectomized female
WT and ERbeta KO mice, where AngII is sta...

## Key facts

- **NIH application ID:** 10045946
- **Project number:** 5I01BX002316-07
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** ELLIS R LEVIN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2014-04-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10045946

## Citation

> US National Institutes of Health, RePORTER application 10045946, Estrogen receptor and the cardiovascular system (5I01BX002316-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10045946. Licensed CC0.

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