Novel peptide that blocks cardiac fibrosis may prevent heart failure

Researchers have shown that a novel therapeutic peptide, pUR4, stopped fibronectin polymerization in a mouse model of heart attack. In turn, this action halted fibrosis and excessive cardiac remodeling, which could prevent heart failure, according to results of a recent study published in Circulation.

“Our data are a strong proof of principle and the first to show that inhibiting fibronectin polymerization preserves heart function, reduces left ventricle remodeling, and limits formation of fibrotic connective tissue,” said the study’s lead investigator Burns Blaxall, PhD, director of translational research, Heart Institute and the Center for Translational Fibrosis Research, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH.

Fibronectin is a protein secreted by cardiac fibroblast cells. Normally, fibronectin helps maintain heart function and repair. But after cardiac injury, quiescent cardiac fibroblast cells are triggered to convert into highly proliferative myofibroblasts, which produce collagen and other components of extracellular matrix involved in myocardial remodeling. Although myofibroblasts initially promote tissue healing after injury, their continued excessive activity—including fibronectin polymerization—results in adverse tissue remodeling and cardiac fibrosis, which ultimately leads to heart failure.

The novel therapy pUR4 is a recombinant peptide with a specific affinity for fibronectin. Dr. Blaxall and coauthors stated that inhibiting fibronectin polymerization may be a new therapeutic strategy for treating cardiac fibrosis and heart failure.

In the first part of the study, the researchers performed in vitro experiments in which they administered pUR4 to myofibroblast cells from mice and humans with heart failure. Results showed that pUR4 inhibited fibronectin formation and blunted the activity of myofibroblasts.

In the second part, the researchers surgically performed a simulated heart attack on mice, and then administered pUR4 for the following 7 days. After 1 week of treatment, the mice had significantly reduced myofibroblast and neutrophil infiltration compared with control mice. Four weeks after cardiac injury, the mice showed significantly less myocardial dysfunction, fibrosis, and cardiac remodeling.

In the third part, the researchers obtained mice bred without the gene for cardiac fibronectin. When these mice were subjected to simulated heart attack, they also had reduced hypertrophy and fibrosis, along with “significant functional cardioprotection.”

Of note, when the researchers gave pUR4 to the genetically altered mice, they found that the treatment offered no additional cardioprotection, “suggesting that the salutary effects of inhibiting fibronectin polymerization may be largely mediated through effects on fibronectin secreted from the cardiac fibroblast lineage,” wrote Dr. Blaxall and coauthors.

They acknowledge that much more research must be done before they know whether the treatment will be safe and effective in humans. In the meantime, they’re working to refine the pUR4 peptide to enhance its capabilities for localized administration to the heart and for extended-release in patients.

This research was funded in part by grants from the National Institutes of Health and an American Heart Association–Great Rivers Affiliate postdoctoral fellowship.