Heart Attack Model Suggests Therapeutic Role for Repair Protein GPNMB

UCLA scientists have identified a protein called glycoprotein nonmetastatic melanoma protein B (GPNMB) as a critical regulator in the heart’s healing process after a heart attack (myocardial infarction; MI). Using animal models, the team, co-led by UCLA professor of medicine and molecular, cell, and developmental biology Arjun Deb, MD, demonstrated that bone marrow-derived macrophage immune cells secrete GPNMB, which binds to the receptor GPR39, promoting heart repair. Their experiments also demonstrated that animals deficient in GPNMB rapidly developed heart failure after MI, and exhibited much higher mortality than control animals. The findings offer a new understanding of how the heart heals itself and could lead to new treatments aimed at improving heart function and preventing the progression to heart failure.

The researchers reported on their finding in Nature Cardiovascular Research, in a paper titled, “Bone-marrow macrophage-derived GPNMB protein binds to orphan receptor GPR39 and plays a critical role in cardiac repair.”

Every 40 seconds, someone in the United States has a heart attack—the leading cause of heart failure. These cardiac events weaken the heart and cause scarring that reduces the heart’s ability to pump blood effectively. “The mammalian heart does not regenerate robustly after myocardial infarction (MI) and heals itself via a fibrotic repair response,” the authors wrote. “And while this scar tissue forms initially to maintain the heart’s structure, it remains permanently, straining the surviving muscle and eventually leading to heart failure.”

Glycoprotein nonmetastatic melanoma protein B was first identified as a gene expressed in a melanoma cell line with low metastatic potential, but since then it has been observed to be expressed in a wide variety of cells, the team continued. Previous clinical studies have indicated that GPNMB has been strongly associated with cardiovascular outcomes of individuals with heart failure. What was not clear, however, was if lacking the protein was directly responsible for the development of heart failure after a heart attack. Previous studies, the investigators continued, “… suggest a role for GPNMB in regulating post-infarction outcomes but the mechanisms of GPNMB effects on the infarcted heart remain unclear.

The important distinction of whether GPNMB is just an associated biomarker or one that plays a causal role could indicate if the protein can be considered a therapeutic target for future studies.

The newly reported studies carried out by Deb, together with first author Sivakumar Ramadoss, PhD, and colleagues, aimed to investigate the role of GPNMB in regulating cardiac repair after MI. Their initial analysis of human population datasets found that GPNMB expression was significantly upregulated in the hearts of individuals with ischemic cardiomyopathy.

In a series of experiments in mouse models, the researchers first established that GPNMB is not natively expressed by the heart itself but is produced by inflammatory cells originating from the bone marrow. After a heart attack, these macrophages travel to the site of injury in the heart, where they express GPNMB.

The team conducted gene knockouts (KOs)—inactivating the GPNMB gene—and bone marrow transplants and observed that mice lacking the GPNMB gene exhibited dramatically worse outcomes after a heart attack, including a higher incidence of heart rupture, a fatal complication also seen in human heart failure patients. Four weeks after a simulated heart attack, 67% of the animals lacking the GPNMB gene exhibited severe fibrosis, or scarring, compared with only 8% of animals in the control group. “Genetic loss-of-function experiments demonstrated that animals deficient in GPNMB exhibited rapid development of heart failure after MI and exhibited much higher mortality than control animals,” they wrote.

Conversely, mice with normal GPNMB expression that were given an additional dose of circulating GPNMB protein showed improved heart function and reduced scarring. “Increasing circulating GPNMB levels through viral delivery improves heart function after MI,” the investigators further pointed out. “Single-cell transcriptomics show that GPNMB enhances myocyte contraction and reduces fibroblast activation.”

In addition to identifying GPNMB as a signaling molecule with effects across various cell types, the researchers uncovered that it binds to GPR39, previously considered an orphan receptor, or a receptor whose binding partner is not known. This interaction triggers a cascade of signals that promote tissue regeneration and limit scarring. “… we identified GPR39 as a receptor for circulating GPNMB, with its absence negating the beneficial effects. These findings highlight a pivotal role of macrophage-derived GPNMBs in post-MI cardiac repair through GPR39 signaling.”

Cardiovascular disease—of which heart failure is a late-stage complication—is a significant health issue, accounting for approximately one-third of all deaths worldwide. Despite its prevalence, there are no available treatments that directly enhance the heart’s ability to repair itself after a heart attack. The team suggests the new study demonstrates the potential of GPNMB as a therapeutic agent, as well as GPR39 as a target, that can limit scarring, improve cardiac function, and prevent heart failure.

This research could also have broader implications for understanding tissue repair in other organs. As GPNMB is expressed in multiple tissues, future studies will explore its role in the repair of the brain, kidneys, and other organs impacted by ischemic injury. “Our observations support the critical role of macrophage-derived GPNMB in regulating cardiac repair after MI,” the authors concluded, noting that, “Although GPNMB was originally identified in cancer cell lines, the roles of GPNMB in regulating cell growth, inflammation, and tissue repair have been recently uncovered. The pro-repair effects of GPNMB observed in our study are broadly consistent with the effects of GPNMB in accelerating repair of bones after fractures.”

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