July 21, 2020

Stopping scar tissue improves healing after heart attack in mice

At a Glance

  • Mice deficient in a protein called type 5 collagen formed larger scars after a heart attack and had worse heart function.
  • Using a drug to disrupt this process let the mice heal normally, suggesting a potential approach to improve heart function after heart attack. 
Electron micrographs of scar tissue Electron microscopy images showing a healthy scar containing type 5 collagen with scar fibers smoothly arranged in parallel (left) and a scar containing no type 5 collagen with disorganized scar fibers (right). Cell / UCLA Broad Stem Cell Research Center

More than 800,000 people in the U.S. have a heart attack each year. With modern treatments, most survive. But a heart attack can cause permanent damage to heart muscle.

After a heart attack, the body’s repair system replaces damaged heart muscle with scar tissue. For reasons that aren’t well understood, some people develop much larger scars after a heart attack than others. People with larger scars have a higher risk of other heart problems and death.

A research team led by Dr. Arjun Deb from the University of California, Los Angeles has been trying to develop methods to improve healing and reduce scarring following heart damage. In their new study, they examined heart tissue from mice to identify which genes are activated after a heart attack.

The study was funded in part by NIH’s National Heart, Lung, and Blood Institute (NHLBI) and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Results were published on July 3, 2020, in Cell.

The researchers found that some of the genes whose activity increased the most after a heart injury encoded for proteins called collagens, which help give tissues strength and structure. Levels of one collagen, called type 5 collagen, were elevated in scar tissue during the early stage of the healing process.

The team next engineered a strain of mice to be deficient in type 5 collagen. Unexpectedly, the mice were substantially more likely to have severe and abnormal scarring after a heart attack. The hearts of mice low in type 5 collagen were also enlarged and performed worse at pumping blood after healing.

The collagen fibers in the scar tissue lacking type 5 collagen, instead of being neatly organized, were in disarray. Testing showed that this scar tissue was more flexible than normal, allowing it to expand. This explains why it is worse at helping the heart beat normally; it can’t properly transfer the forces needed in a beating heart.

The team also found that scars in the mice with type 5 collagen deficiency contained higher numbers of cells called myofibroblasts. Myofibroblasts are thought to be the main cell type responsible for producing the proteins that form scar tissue.

Further work showed that the creation of new myofibroblasts was triggered by the flexible scar tissue itself through proteins called integrins. Integrins are receptors on the surface of cells that can sense mechanical forces. Overexpansion of the scar tissue signals cells within the scar tissue, via integrin, to make more myofibroblasts. These, in turn, lay down more scar tissue. Thus the lack of type 5 collagen, by changing the mechanical properties of the scar, causes myofibroblasts to then expand the scar.

The research team injected a drug that blocks integrins (cilengitide) into mice deficient in type 5 collagen. They found that the drug prevented abnormal scarring after a heart attack. Mice given the drug produced fewer myofibroblasts, and their heart function was similar to that of mice with normal type 5 collagen levels.

“Given the clear correlation between scar size and survival rates, we set out to understand why some hearts scar more than others. If we can reduce this scarring, we can greatly improve survival,” Deb says.

Cilengitide was developed as a cancer treatment and is not approved for use after a heart attack in people. The researchers now hope to study it further for heart disease. They also plan to test the drug as a treatment for Ehlers-Danlos syndrome, a rare disease caused by deficiency in type 5 collagen.

—by Sharon Reynolds

Related Links

References: Type V Collagen in Scar Tissue Regulates the Size of Scar after Heart Injury. Yokota T, McCourt J, Ma F, Ren S, Li S, Kim TH, Kurmangaliyev YZ, Nasiri R, Ahadian S, Nguyen T, Tan XHM, Zhou Y, Wu R, Rodriguez A, Cohn W, Wang Y, Whitelegge J, Ryazantsev S, Khademhosseini A, Teitell MA, Chiou PY, Birk DE, Rowat AC, Crosbie RH, Pellegrini M, Seldin M, Lusis AJ, Deb A. Cell. 2020 Jul 3:S0092-8674(20)30807-2. doi: 10.1016/j.cell.2020.06.030. Online ahead of print. PMID: 32621799.

Funding: NIH’s National Heart, Lung, and Blood Institute (NHLBI), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Center for Advancing Translational Science (NCATS), and National Institute of General Medical Sciences (NIGMS); Department of Defense; National Science Foundation; Eli and Edythe Broad Stem Cell Center; California Nanosystems Institute; James Eason Cardiovascular Discovery Fund.