Target protein identified for improving heart attack treatment
A new study led by researchers at Washington State University has
identified a protein that could be the key to improving treatment outcomes
after a heart attack.
Published in the Journal of Biological Chemistry, the
research suggests that protein kinase A (PKA) plays a role in heart muscle cell
necrosis, a major type of cell death that commonly occurs after reperfusion
therapy, the treatment used to unblock arteries and restore blood flow after a
heart attack.
“Our study has found that turning off a gene that controls this
protein activity increased necrotic cell death and led to more heart injury and
worse heart function following heart attack in a rodent model,” said study
author Zhaokang Cheng, an assistant professor in the WSU College of Pharmacy
and Pharmaceutical Sciences. “With further research, this discovery could
ultimately lead to the development of a small-molecule drug that could
intervene in that pathway to limit or prevent heart muscle cell death after
reperfusion therapy.”
Such a drug could help reduce heart injury and increase the survival and
lifespan of heart attack victims, Cheng said. Every year, about 800,000 people
in the U.S. have a heart attack, which amounts to one heart attack occurring
every 40 seconds.
Reperfusion therapy, which uses clot-dissolving drugs or mechanical
means to unblock clogged arteries, has long been the most effective treatment
for heart attack. Though it significantly reduces heart damage, patients
treated with this therapy still experience some damage, about half of which
actually results from the treatment itself. This is because the rapid restoration
of blood flow into oxygen-deprived heart tissues can lead to a swift rise in
free radicals. When left unchecked, this surge of free radicals induces
oxidative stress, which can cause heart muscle cell death and heart injury as
part of a condition known as ischemia/reperfusion injury.
Though scientists have long considered necrosis to be a passive,
unavoidable form of cell death, recent studies have suggested that some forms
of it happen in a highly regulated manner that could potentially be targeted
for treatment. Little has been known about how this type of cell death is
regulated, however, which is what prompted Cheng to take a closer look.
He and his team had previously screened more than 20,000 genes to look
for ones that appeared to either suppress or promote necrotic cell death. One
gene that stood out to them as warranting further study was PRKAR1A, which
helps regulate PKA activity by encoding a protein known as PKA regulatory
subunit R1alpha.
So the researchers conducted a series of experiments to validate whether
the R1alpha protein can regulate necrotic cell death in a rodent model. They
found that turning off the PRKAR1A gene increased cell death,
both in cultured cells and in mice. Mice lacking the gene also had more heart
injury and worse heart function after heart attack, as compared to wild-type
mice.
Cheng explained that, under normal circumstances, the rapid increase of
free radicals after heart attack treatment triggers the heart to launch its
antioxidant defense system, the built-in protective mechanism that helps keep
free radicals in check. What their new study findings suggest is that the
antioxidant defense system cannot be launched as effectively when the R1alpha
protein is removed from the heart, resulting in more oxidative stress, which
leads to cell death and heart injury.
He explained that the R1alpha protein binds to another type of protein
known as PKA catalytic subunits to keep PKA activity in check. When R1alpha is
removed, the catalytic subunits are uncontrolled and PKA activity increases,
which Cheng believes is what prevents the activation of the antioxidant defense
system. This suggests that use of a small-molecule compound that selectively
inhibits PKA activity could potentially block necrotic cell death and lead to better
outcomes after heart attack treatment.
Though Cheng said he hoped their research would eventually allow them to
test such a compound in an animal model, the next step they are pursuing is to
determine whether there are other mechanisms by which PKA regulates necrotic
cell death aside from the antioxidant defense system.
Journal Reference:
- Yuening Liu,
Jingrui Chen, Peng Xia, Constantine A. Stratakis, Zhaokang Cheng. Loss
of PKA regulatory subunit 1α aggravates cardiomyocyte necrosis and myocardial ischemia/reperfusion
injury. Journal of Biological Chemistry, 2021; 100850
DOI: 10.1016/j.jbc.2021.100850