Arjun Deb Lab/UCLA
Heart muscle cells surrounding the damaged tissue after a heart attack.
FINDINGS
UCLA scientists have identified the protein GPNMB as a critical regulator in the heart's healing process after a heart attack.
Using animal models, they demonstrate that bone marrow-derived immune cells called macrophages secrete GPNMB, which binds to the receptor GPR39, promoting heart repair. These 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.
BACKGROUND
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. 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.
Previous clinical studies have indicated that GPNMB, or glycoprotein non-metastatic melanoma protein B, 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. This important distinction — whether GPNMB is just an associated biomarker or one that plays a causal role — determines if the protein can be considered a therapeutic target for future studies.
METHOD
Utilizing 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 — 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. Conversely, mice with normal GPNMB expression that were given an additional dose of circulating GPNMB protein showed improved heart function and reduced scarring. 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.
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.
IMPACT
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 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.
AUTHORS
Dr. Arjun Deb, a professor of medicine and molecular, cell and developmental biology; director of the UCLA Cardiovascular Research Theme at the David Geffen School of Medicine at UCLA; and member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, led the study. A full list of contributors is available in the journal.
JOURNAL
The study was published in Nature Cardiovascular Research.
FUNDING
This study was supported by grants from the National Institutes of Health.
DISCLOSURES
The therapeutic potential of GPNMB described in this study is under investigation and has not yet been tested in human clinical trials. The research findings are based on preclinical models, and further studies are required to assess safety and efficacy in humans.
