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Boosting the Heart’s Natural Capacity to Recuperate After Heart Attack with Key Protein

By LabMedica International staff writers
Posted on 27 Oct 2014
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Image: Fibroblasts (red) express endothelial markers (green), making the heart cells in mice appear yellow. The green blood vessels running horizontally are partly composed of red/yellow cells, suggesting that fibroblasts are incorporated into blood vessels (Photo courtesy of UNC – University of North Carolina).
Image: Fibroblasts (red) express endothelial markers (green), making the heart cells in mice appear yellow. The green blood vessels running horizontally are partly composed of red/yellow cells, suggesting that fibroblasts are incorporated into blood vessels (Photo courtesy of UNC – University of North Carolina).
By increasing up the levels of a well-known protein in the heart, researchers have discovered a new way to generate more blood vessels following a heart attack.

Researchers from the University of North Carolina (UNC) School of Medicine (Chapel Hill, NC, USA) have discovered that cells called fibroblasts, which typically give rise to scar tissue after a heart attack, can be converted into endothelial cells, which generate blood vessels to supply oxygen and nutrients to the injured regions of the heart, thereby greatly lessening the damage done following an attack. This switch is fueled by p53, a well-known tumor-suppressing protein. The UNC researchers showed that increasing the level of p53 in scar-forming cells significantly reduced scarring and improved heart function after heart attack.

The finding, which was published October 15, 2014, in the journal Nature, demonstrated that it is possible to limit the damage brought about by heart attacks. “Scientists have thought that fibroblasts are terminally differentiated, meaning they can’t adopt the fate of other kinds of cells; but our study suggests this may not be entirely true,” said Eric Ubil, PhD, a postdoctoral fellow at UNC and first author of the study. “It appears that injury itself can induce fibroblasts to change into endothelial cells so the heart heals better. We found a drug that could push this process forward, making even more endothelial cells that help form blood vessels. The results were truly amazing in mice, and it will be exciting to see if people respond in the same way.”

After a heart attack, fibroblasts replace injured heart muscle with scar tissue. This scarring can harden the walls of the heart and lessen its ability to pump blood throughout the body. In the meantime, endothelial cells create new blood vessels to improve circulation to the damaged area. However, sometimes these endothelial cells naturally turn into fibroblasts instead, adding to the scarring.

Dr. Ubil and his colleagues speculated if the switch ever flipped the other way—could fibroblasts transformed into endothelial cells. To explore this theory, they induced heart attacks in mice and then studied the fibroblasts to see if the cells expressed markers characteristic of endothelial cells. To their amazement, nearly one-third of the fibroblasts in the area of the cardiac injury expressed these endothelial markers. The researchers discovered that the endothelial cells generated from fibroblasts did indeed give rise to functioning blood vessels.

Next, Dr. Ubil and colleagues set out to identify the molecule that triggered the switch. Because a heart attack is such a stressful event, Dr. Ubil created a list of genes that were known to be involved in cellular responses to stress. Capping the list was p53, a protein frequently called the “guardian of the genome” because it causes damaged, out of control cells to commit suicide, or apoptosis, which reduces the probability that they will go on to form tumors.

“As luck would have it, that was the first gene I tried, and that was the last gene I tried,” said Ubil, who conducted this research as a graduate student in the laboratory of senior study author Arjun Deb, MD, a former faculty member in the department of cell biology and physiology.

Dr. Ubil found that p53 was “activated or overexpressed in the fibroblasts after heart injury and this seemed to regulate fibroblasts becoming endothelial cells. He and colleagues supposed that if the p53 protein was responsible for the positive switch, then blocking it in mice would halt the transition from scar-forming cells to blood vessel-forming cells. Their research revealed that knocking out the p53 gene in scar-forming cells in adult mice decreased the number of cells making the switch by 50%.

Similarly, the researchers reasoned that boosting the level of p53 would increase the number of fibroblasts that would turn into endothelial cells. Because p53 is frequently mutated or lost in cancer cells, a number of compounds have been devised to raise its levels as a possible anticancer treatment. The researchers chose one such research agent called RITA (reactivation of p53 and induction of tumor cell apoptosis) and used it to treat mice for a few days after cardiac injury. The drug had drastic results, doubling the number of fibroblasts that converted into endothelial cells. Meaning, instead of just 30% of fibroblasts naturally switching into endothelial cells, 60% made the switch.

“The treated mice benefited tremendously,” Dr. Ubil said. “There was such a huge decrease in scar formation. We checked the mice periodically, from three days to fourteen days after treatment. They had more blood vessels at the site of injury, and their heart function was better. By increasing the number of blood vessels in the injury region, we were able to greatly reduce the effects of the heart attack.”

Dr. Ubil reported his study revealed that this could be an innovative approach for treating heart attacks. However, he warned that any treatments based on the discovery outlined in Nature are many years away. “But our work shows it’s possible to change the fate of scar-forming cells in the heart, and this could potentially benefit people who have heart attacks,” Dr. Ubil said.

Dr. Deb added, “We are also currently investigating whether such an approach could be applied for treating scarring in other organs after injury.”

Related Links:

University of North Carolina School of Medicine


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