Key Regulator of Heart Repair

UCLA researchers identified the protein GPNMB as a key regulator in the heart’s healing process following a heart attack.

Researchers using animal models have shown that GPNMB, a protein secreted by bone marrow-derived immune cells known as macrophages, binds to the receptor GPR39, promoting heart repair. This discovery offers a new perspective on the heart’s self-healing capabilities and could lead to innovative therapies to improve heart health and prevent heart failure.

Background

Heart attacks, which occur every 40 seconds in the US, are the leading cause of heart failure. These events damage the heart, weakening its ability to pump blood and causing scarring. Initially, scar tissue forms to stabilize the heart’s structure, but it remains indefinitely, placing stress on the remaining muscle and eventually leading to heart failure.

Previous studies have shown that GPNMB (glycoprotein non-metastatic melanoma protein B) is closely associated with heart failure outcomes. However, it was unclear whether low levels of GPNMB directly contributed to heart failure after a heart attack. Determining if GPNMB plays a causal role, rather than simply acting as a biomarker, is essential for identifying it as a potential therapeutic target.

Method

The researchers first demonstrated that GPNMB is produced by inflammatory cells from the bone marrow, not by the heart itself. Following a heart attack, these macrophages migrate to the heart’s damaged areas, where they express GPNMB.

Using mouse models, the team conducted bone marrow transplants and gene knockouts to deactivate the GPNMB gene. They observed that mice lacking GPNMB had significantly worse outcomes after a heart attack, including a higher risk of heart rupture—a fatal outcome also seen in heart failure patients. Conversely, mice with normal GPNMB expression and additional circulating GPNMB had better heart function and reduced scarring. Four weeks after a simulated heart attack, 67% of GPNMB-deficient mice showed severe fibrosis (scarring), compared to only 8% in the control group.

Impact

The researchers identified GPR39 as the binding partner for GPNMB. Previously considered an orphan receptor, GPR39 triggers a signaling cascade upon binding with GPNMB, which reduces scarring and promotes tissue regeneration.

Heart failure, a severe stage of cardiovascular disease, is responsible for about one-third of all deaths worldwide. Despite its prevalence, no treatments currently exist to enhance the heart’s healing after a heart attack. This study suggests that GPNMB, as a therapeutic agent, and GPR39, as a target, could reduce scarring, improve heart function, and prevent heart failure.

Furthermore, this research could extend beyond cardiac health. Since GPNMB is expressed in various tissues, future studies will investigate its role in repairing other organs affected by ischemic injury, including the kidneys and brain.

Source:
Journal reference:

‌Ramadoss, S., et al. (2024) Bone-marrow macrophage-derived GPNMB protein binds to orphan receptor GPR39 and plays a critical role in cardiac repair. Nature Cardiovascular Research. doi.org/10.1038/s44161-024-00555-4.

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