Scientists have discovered that the protein GPNMB plays a vital role in the heart’s recovery process following a heart attack.
UCLA scientists have discovered that the protein GPNMB plays a vital role in the heart’s recovery process following a heart attack.
Through research using animal models, they showed that macrophages, which are immune cells derived from bone marrow, release GPNMB. This protein attaches to the receptor GPR39, which aids in heart repair. These insights provide a new perspective on how the heart heals and could pave the way for new therapies focused on enhancing heart functionality and avoiding heart failure.
In the United States, someone suffers a heart attack every 40 seconds, making it the leading cause of heart failure. These events damage the heart and create scar tissue that hinders its ability to efficiently pump blood. Although this scar tissue initially forms to preserve the heart’s structure, it becomes permanent, putting extra pressure on the remaining heart muscles and ultimately resulting in heart failure.
Earlier clinical studies have linked GPNMB, or glycoprotein non-metastatic melanoma protein B, to cardiovascular outcomes in heart failure patients. However, it was uncertain whether the absence of this protein directly caused heart failure after a heart attack. This distinction between GPNMB being an associated biomarker or having a causal role determines its potential as a target for future therapeutic approaches.
By using mouse models, the researchers determined that GPNMB is not naturally produced by the heart but is generated by inflammatory cells from the bone marrow. After a heart attack, these macrophages move to the heart’s injury site, where they produce GPNMB.
The research team performed gene knockouts to deactivate the GPNMB gene and conducted bone marrow transplants. They noted that mice without the GPNMB gene had significantly poorer outcomes after a heart attack, including a greater risk of heart rupture, a serious complication also experienced by humans with heart failure. On the other hand, mice with normal levels of GPNMB that received an extra dose of this circulating protein showed improved heart function and less scarring. Four weeks after a simulated heart attack, 67% of the mice lacking the GPNMB gene displayed severe fibrosis, compared to only 8% in the control group.
Besides recognizing GPNMB as a signaling molecule affecting multiple cell types, the researchers found that it binds to GPR39, which was previously regarded as an orphan receptor, meaning its binding partner was unknown. This interaction sets off a series of signals that foster tissue regeneration and minimize scarring.
Cardiovascular disease, with heart failure being a late-stage complication, is a major health concern, responsible for about one-third of global deaths. Despite its high occurrence, there are no current treatments that effectively improve the heart’s capacity to heal post-heart attack. This new research highlights GPNMB’s potential as a therapeutic option, alongside GPR39 as a target that could reduce scarring, enhance heart function, and help avert heart failure.
Moreover, this research may extend its relevance to the healing processes of other organs as GPNMB is found in several tissues. Future investigations will look into its role in repairing the brain, kidneys, and other organs affected by ischemic injury.
The study was led by Dr. Arjun Deb, a professor in medicine and molecular, cellular, and developmental biology; the director of the UCLA Cardiovascular Research Theme at the David Geffen School of Medicine at UCLA; and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research.
It’s important to note that the therapeutic possibilities of GPNMB outlined in this study are still under investigation and have not yet been tested in human clinical trials. The findings are based on preclinical models, and further research is needed to evaluate safety and effectiveness in human subjects.
