BOOSTING HEART'S NATURAL ABILITY TO RECOVER AFTER HEART ATTACK
Researchers from the
UNC School of Medicine have discovered that cells called fibroblasts, which
normally give rise to scar tissue after a heart attack, can be turned into
endothelial cells, which generate blood vessels to supply oxygen and nutrients
to the injured regions of the heart, thus greatly reducing the damage done
following heart attack.
This switch is driven
by p53, the well-documented 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 today in the journal Nature, shows that it is possible to
limit the damage wrought by heart attacks, which strike nearly one million
people in the United States each year. Heart disease accounts for one in four
deaths every year.
"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 Nature 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 damaged heart muscle with scar tissue. This scarring can
harden the walls of the heart and lessen its ability to pump blood throughout
the body. Meanwhile, 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.
Ubil and his
colleagues wondered if the switch ever flipped the other way -- could
fibroblasts turn into endothelial cells. To explore this idea, they induced
heart attacks in mice and then studied the fibroblasts to see if the cells
expressed markers characteristic of endothelial cells. To their surprise,
almost a third of the fibroblasts in the area of the cardiac injury expressed
these endothelial markers. The researchers found that the endothelial cells
generated from fibroblasts actually gave rise to functioning blood vessels.
Next, Ubil and
colleagues wanted to identify the molecule that triggered the switch. Because a
heart attack is such a stressful event, Ubil created a list of genes that were
known to be involved in cellular responses to stress. Topping the list was p53,
a protein often called the "guardian of the genome" because it causes
damaged, out of control cells to commit suicide, or apoptosis, which reduces
the likelihood 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 the research as a graduate student in the
laboratory of former UNC faculty member and senior study author Arjun Deb, MD.
Ubil found that p53
was "turned on" or overexpressed in the fibroblasts after heart
injury and this seemed to regulate fibroblasts becoming endothelial cells. He
and colleagues figured 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 experiments revealed that knocking
out the p53 gene in scar-forming cells in adult mice decreased the number of
cells making the switch by 50 percent.
Likewise, the
researchers rationalized that upping the level of p53 would increase the number
of fibroblasts that would turn into endothelial cells. Because p53 is often
mutated or lost in cancer cells, a number of compounds have been designed to
increase its levels as a possible anti-cancer treatment. The researchers picked
one such experimental drug 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 dramatic results, doubling the number of fibroblasts that
turned into endothelial cells. That is, instead of just 30 percent of
fibroblasts naturally switching into endothelial cells, 60 percent made the
switch.
"The treated mice
benefited tremendously," 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."
Ubil said his study
shows that this could be a novel strategy for treating heart attacks. However,
he cautioned 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," Ubil said.
Deb added, "We
are also currently investigating whether such an approach could be applied for
treating scarring in other organs after injury."
The research was
supported by the American Heart Association and the National Institutes of
Health.
Eric Ubil, PhD, is now
a postdoctoral fellow at the UNC Lineberger Comprehensive Cancer center. Other
UNC co-authors include graduate student Francesca Bargiacchi and Mauricio Rojas,
MD, MPH. Arjun Deb, MD, is now on the faculty at UCLA.
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