# Role of eosinophil cationic proteins in cardiac hypertrophy

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $699,381

## Abstract

Coronary heart diseases remain the leading cause of deaths in the US. Despite the success of lipid lowering,
residual risk remains. Current clinical studies support the participation of inflammation in cardiovascular
diseases (CVD). Eosinophils (EOS) develop in the bone-marrow under the control of transcription factor
GATA1. These granule cells accumulate in blood or at the site of inflammation. Blood EOS counts and EOS
cationic protein (ECP) levels associate positively with the major CVD risk factors, prevalence, and mortality.
Yet other studies reported reduced blood EOS counts and ECP levels in patients with major adverse cardiac
events and heart failure (HF). Therefore, the role for EOS in human CVD remains unsettled. We reported that
patients with hypertension showed positive association between blood EOS counts and hypertrophic measures.
Using transverse aortic constriction (TAC)- and β-adrenergic receptor agonist isoproterenol (ISO)-induced
cardiac hypertrophy and HF in EOS-deficient ∆dblGATA mice and in diphtheria toxin-induced EOS-depleted
iPHIL mice, we demonstrated a reparative role of EOS in cardiac hypertrophy and HF by producing IL4 and
cationic protein (mEar1). Mechanistic studies reported a role for EOS-derived IL4 and cationic proteins (mEar1,
ECP) in blocking cardiomyocyte hypertrophy and apoptosis, and in inhibiting cardiac fibroblast TGF-β signaling
and fibrosis. EOS granules contain cytokines, chemokines, growth factors, in addition to cationic proteins. To
avoid ambitious concern, we will only study EOS cationic proteins in this proposal, as many other cells in
hypertrophic heart also express these EOS cytokines, chemokines, and growth factors. Human EOS cationic
protein ECP was identified 50 years ago and has been used as a biomarker for many human diseases, but it
remains unknown whether and how ECP contributes to human diseases. Our preliminary studies showed that
cardiomyocytes express bone morphogenetic protein receptor BMPR-1A and 1B, but not BMPR-2. In contrast,
cardiac fibroblasts express BMPR-2 but not BMPR-1A or 1B. mEar1 uses BMPR-1A and 1B on
cardiomyocytes as its receptor to activate the Smad-1/5/8 signaling and to block ISO-induced cardiomyocyte
hypertrophy, but uses BMPR-2 on cardiac fibroblasts to block TGF-β-induced Smad2/3 signaling and fibrotic
protein expression. In this proposal, we hypothesize that EOS protect heart from hypertrophy and HF by
releasing cationic proteins to block cardiomyocyte hypertrophy and apoptosis and to inhibit cardiac fibroblast
activation. EOS cationic proteins (mouse mEar1 and human ECP and EDN) exert their cardioprotective roles
using BMPR-1A and 1B as their receptors on cardiomyocytes and BMPR-2 as their receptor on cardiac
fibroblasts. Maintenance of functional receptors for EOS cationic proteins is essential to the cardioprotective
role of human or mouse EOS. We propose two Aims to explore the molecular mechanisms by which EOS
cationic proteins protect cardiomyocytes from hy...

## Key facts

- **NIH application ID:** 10890866
- **Project number:** 5R01HL166538-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Peter Libby
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $699,381
- **Award type:** 5
- **Project period:** 2023-07-19 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890866

## Citation

> US National Institutes of Health, RePORTER application 10890866, Role of eosinophil cationic proteins in cardiac hypertrophy (5R01HL166538-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10890866. Licensed CC0.

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