Researchers have identified a gene that controls the behavior of a particular type of cardiac macrophage responsible for excessive scarring in the early stages of common heart diseases.
When the gene called WWP2 is blocked, heart function improves and scar tissue formation slows down, delaying progression to heart failure.
“As with non-ischemic cardiomyopathies, scarring or fibrosis of the heart is a progressive condition and a global health concern,” says Enrico Petretto, MD, director of Duke-NUS’ Center for Computational Biology and the school’s Cardiovascular and Systems Geneticist. Metabolic Disorders (CVMD) program.
“In its earliest stages, it is characterized by the inflammatory stage, so intervening at this point can significantly delay the progression of the disease.”
“Targeting World War II is like throwing a blanket over a fire; it removes oxygen from the flames before the whole house burns.”
Petretto and colleagues in Singapore, China and the United Kingdom have studied the function of WWP2 in fibrotic diseases for several years and first discovered that it is an important scarring trigger when expressed in fibroblasts, scar tissue-forming cells.
In their latest published findings, Nature Communicationteam turned their attention to the early stage of the disease.
Using single-cell RNA sequencing, the team found that when fibrosis is triggered, a wide variety of different macrophages (immune cells that scavenge foreign substances in the body) are activated in a preclinical model of heart disease.
While macrophages are mostly known for their role in removing cancer cells, microbes and cellular debris, they also help regenerate healthy muscle cells. However, a subset of these cardiac macrophages is controlled by WWP2. These WWP2-expressing macrophages actively promote scarring by triggering local heart cells (fibroblasts) to produce collagen in an uncontrolled manner, triggering scar tissue formation.
“In this latest study, we focused on the ‘cross talk’ that occurs between macrophages and fibroblasts during the early stages of fibrogenesis,” says Chen Huimei, senior research fellow at the CVMD Program. paper.
“We found that when WWP2 is expressed in macrophages, these cells ‘irritate’ fibroblasts, leading to uncontrolled scarring.”
On the other hand, when macrophages did not express WWP2, the team observed reduced infiltration of pro-fibrotic macrophages into the heart, and the action of repair macrophages was better sustained with clear beneficial effects on cardiac tissue and function. disease.
“Targeting WP2 is like throwing a blanket over a fire; it removes oxygen from the flames before the entire house burns,” explains systems biologist and associate professor Jacques Behmoaras, co-author of the study, from the CVMD program. “Blocking the function of WWP2 in this subset of cardiac macrophages is sufficient to slow or even stop scarring.”
The team is developing a small molecule inhibitor against WWP2 that can do just that. Rather than indiscriminately depleting all macrophages that show harmful effects, the team specifically targets WWP2, which works on these pro-fibrotic macrophages and activated fibroblasts to stop scarring in the damaged heart.
“Because WWP2 plays a dual role in the formation of scar tissue and ‘hits two birds with one stone’, it blocks tissue, reducing inflammation and scarring at the same time. With the added benefit of increasing beneficial tissue repair macrophages, WWP2 is making it a very attractive therapeutic target,” adds the study senior. by Petretto.
“We are now developing small molecule inhibitors that target a specific form of the WWP2 protein that have shown promising anti-fibrotic results in cells. We believe they may have therapeutic potential to treat fibrotic conditions such as non-ischemic cardiomyopathies and be effective in other fibrotic diseases involving WWP2. “