Epigenetic regulation of MFAP5 by the FN1–ITGAV/ITGB1–EGR1 axis in border zone fibroblast activation: mechanistic insights and therapeutic potential in post–myocardial infarction scar expansion

• Applicant: Privatdozent Dr. Xingbo Xu, Ph.D.
• Subject Area: Cardiology, Angiology ; Cell Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 574478878

Heart attacks (also called myocardial infarctions, or MI) occur when blood flow to part of the heart is blocked, damaging heart muscle. Even when patients survive the initial event, many develop long-term complications such as heart failure. One major cause is the formation of stiff scar tissue, known as cardiac fibrosis. Currently, no treatments directly target or prevent this type of fibrosis. In our project, we are studying a gene called MFAP5, which we found to be highly active in a specific heart region after MI—the border zone, between damaged and healthy tissue. The border zone plays a pivotal role in post-MI remodeling, influencing infarct expansion, fibrosis, cardiomyocyte hypertrophy, tissue structure, and the risk of arrhythmias and sudden cardiac death. Our early findings suggest that MFAP5 may play an important role in how scar tissue forms and expands after a heart attack. We believe that understanding this gene’s function could open up new ways to reduce or prevent harmful scar expansion in the heart. To test this idea, our project has several goals: 1. Understand how MFAP5 becomes active We aim to find out what triggers the MFAP5 gene in heart cells after a heart attack. We have discovered that a protein called fibronectin (FN1), released by fibroblasts in the damaged area, may activate MFAP5 in neighboring cells through a chain of signals. We will investigate this signaling process and look at how the gene is turned on at the DNA level, including changes in DNA methylation (a form of gene regulation). 2. Test the role of MFAP5 using genetically modified mice We will use MFAP5 knockout mice—mice lacking the MFAP5 gene—to assess how their hearts respond to MI compared to normal mice. We expect these mice to show reduced scarring and better heart function. We will use imaging, histology, and heart function tests to measure the effects. 3. Evaluate the effects of blocking MFAP5 with an antibody To explore a possible treatment approach, we will use an antibody that blocks MFAP5 function. This will be tested in normal mice after inducing a heart attack, to see if it can reduce the formation of fibrotic scar tissue and the associated decline in heart function. 4. Use a 3D human heart tissue model To make our findings more relevant to human health, we will use a laboratory-grown, 3D heart tissue model made from human stem cells. This model allows us to simulate fibrosis and test the impact of MFAP5 manipulation on tissue stiffness and gene expression. Overall, this project aims to explain how MFAP5 contributes to the scar tissue formation and expansion after a heart attack, and whether it could be a target for future treatments to protect the heart. Our findings could help pave the way for new therapies that reduce the risk of heart failure and improve recovery after heart attacks.

• DFG Programme: Research Grants