# Role of GPNMB in cardiac remodeling

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $702,950

## Abstract

PROJECT SUMMARY/ABSTRACT
The mammalian heart has a poor ability to regenerate heart muscle following myocardial infarction and dead
cardiac muscle is replaced by scar tissue. Scar tissue is non-contractile, induces adverse cardiac remodeling
and leads to dilatation of cardiac chambers, cardiomyocyte hypertrophy and development of heart failure.
Despite optimal use of cardiovascular drugs, adverse remodeling following myocardial infarction contributes to
40% of all new case of heart failure. There thus exists an immense need to identify new targets for attenuating
post infarct remodeling and development of heart failure. In this application, we identify GPNMB (Glycoprotein
Non-Metastatic Melanoma Protein B) as a novel target for attenuating post infarct cardiac remodeling. We
identified the protein using a systems genetics approach, in which a panel of inbred strains of mice were
studied for heart failure traits in response to isoproterenol treatment. We demonstrate that GPNMB expression
increases by an order of magnitude in infarcted murine hearts and regulates wound healing events in the heart
early following injury. We show that macrophages that are recruited to the infarcted heart are the primary
source of GPNMB expression. Using loss and gain of function approaches, we demonstrate that GPNMB
activates cardiac fibroblasts and induces profound cardiomyocyte hypertrophy. In contrast, genetic deletion of
GPNMB leads to attenuation of post infarct cardiac remodeling and is associated with better preservation of
cardiac function. We also provide data that GPNMB plasma levels in humans is strongly associated with heart
failure strengthening a causal relationship between GPNMB and the development of post infarct heart failure.
Considering these observations, we hypothesize that GPNMB regulates (i) post infarct cardiac remodeling and
(ii) inhibition of GPNMB will attenuate post infarct cardiac remodeling. We have assembled a multi-disciplinary
team comprising expertise in cardiac physiology, genetics and extracellular matrix biology to interrogate the
role and mechanisms of GPNMB in regulating post infarct cardiac remodeling. In the first aim, we will examine
the role of GPNMB on cardiac remodeling with gain and loss of function approaches. In the second aim, we will
identify mechanisms of GPNMB activation and use physico-chemical studies to determine the receptor to
which GPNMB ligand binds and GPNMB domains critical for binding. In the third aim, we will use mouse and
human genetics approaches to model biological pathways influenced by GPNMB and interrogate common
downstream signaling pathways that mediate GPNMB effects on myocytes and non-myocytes. Finally, we will
determine whether pharmacological targeting of GPNMB can be therapeutic strategy for attenuating adverse
remodeling after cardiac injury.

## Key facts

- **NIH application ID:** 10116941
- **Project number:** 1R01HL152176-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Arjun Deb
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $702,950
- **Award type:** 1
- **Project period:** 2020-12-20 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116941

## Citation

> US National Institutes of Health, RePORTER application 10116941, Role of GPNMB in cardiac remodeling (1R01HL152176-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10116941. Licensed CC0.

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