Studying the aftermath of a heart attack, scientists at Duke-NUS have identified a gene that provokes out-of-control scarring in the heart of people with cardiovascular diseases, such as cardiomyopathy and congenital heart diseases. This excessive scarring can eventually lead to heart failure.
“One in three deaths in Singapore is due to cardiovascular diseases, in particular cardiovascular diseases that have progressed to heart failure,” explained systems geneticist Enrico Petretto, an associate professor with Duke-NUS’ Cardiovascular and Metabolic Disorders Programme. “If we can intervene at the early stage of the disease by manipulating this gene therapeutically then we can stop or delay the excessive formation of the scar and therefore provide a better life for patients.”
The gene, called WWP2, controls the behaviour of cardiac macrophages, a specific type of immune cell in the heart, that incite scarring in the early phases of heart disease. It also regulates the cells that produce scar tissue, called fibroblasts.
“Because WWP2 plays a double role in the formation of scar tissue, blocking it ‘kills two birds with one stone’, by dampening inflammation and scarring at once,” added Petretto, who has been studying the function of WWP2 with colleagues in Singapore, China and the UK for several years. Having demonstrated the role of WWP2 in regulating fibroblast, the team’s most recent discovery, published in Nature Communications, focused on the cellular events during the early stages of the disease.
Using single-cell RNA sequencing, they found that when fibrosis is triggered, a wide range of different macrophages—immune cells that clear foreign material 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 to regenerate muscle cells. However, a subset of these cardiac macrophages expressed WWP2, which actively incited local fibroblasts to produce collagen in an uncontrolled manner instead, fuelling scar tissue formation.
“In this latest study, we focused on the ‘cross-talk’ that happens between macrophages and fibroblasts in the early stages of fibrogenesis,” said first author
Dr Chen Huimei, a senior research fellow with the Programme. “We found that when WWP2 is expressed in macrophages, these cells ‘irritate’ fibroblasts which leads to uncontrolled scarring.”
Blocking the expression of WWP2 in these macrophages, the team observed that fewer pro-fibrotic macrophages infiltrated the heart. The action of macrophages that help the repair process was also better sustained with clear positive effects on cardiac tissue and function during the later stages of the disease.
“Targeting WWP2 is like throwing a blanket over the fire—it removes the oxygen from the flames before the whole house burns down,” explained systems biologist
Jacques Behmoaras, an associate professor with the Programme and a reader in immunogenetics at Imperial College London. “Blocking WWP2’s function in this subset of cardiac macrophages is enough to slow—or even stop—the scarring.”
Petretto, who is also the director of Duke-NUS’
Centre for Computational Biology, combined his different expertises and used artificial intelligence to identify the most promising small molecule inhibitor against WWP2. Rather than depleting all macrophages indiscriminately, which was shown to have deleterious effects, their strategy is to target WWP2, which works specifically on pro-fibrotic macrophages and activated fibroblasts to halt scarring of the damaged heart.
“We believe these inhibitors could hold therapeutic potential for treating fibrotic conditions like non-ischaemic cardiomyopathies and may prove effective in other fibrotic diseases where WWP2 is involved,” said Petretto.
Written by Yu Zehan, edited by Nicole Lim