The discovery may lead to new ways to save that dying
tissue.
It is the stoppage of blood flow and resulting loss
of oxygen to the heart that causes chest pain during
cardiac events. Clinicians' first order of business is
restoring that flow with medicine or other noninvasive
procedures, or even an invasive procedure, such as
placement of a stent or balloon to open a blocked
vessel.
But the rush of blood – and the oxygen it carries –
that restores a heart's beat and relieves the pain can
also damage tissue and weaken the heart's function
because cardiac cells die in the process. And like
brain cells, cardiac cells take a long time for the
body to replace, so the damage is difficult to repair.
Researchers at Ohio State University Medical Center
have traced this cell-death signal to the
mitochondria, the principal energy source of cells,
through a specialized technique. In experiments,
cardiac cell mitochondria were isolated and subjected
to ischemia and reperfusion – the blockage and restart
of blood flow. The researchers hope that identifying
the origin of the cell-death signal will improve the
chances of finding a way to stop the signal, reducing
the damage associated with restored blood flow to the
heart.
The results were published in the October issue of
the Journal of Molecular and Cellular Cardiology.
“This form of cardiac cell death is a major medical
and health issue. The patient has severe pain from the
loss of blood flow and oxygen to the heart, so we
cannot do anything other than clear that artery to
restore the blood and oxygen. But when that is done,
the patient loses cardiac cells. It's a paradox,” said
senior study author Pedram Ghafourifar, associate
professor of surgery
and pharmacology and director of basic science
research in the division of vascular surgery at Ohio
State 's Medical Center.
“The mitochondria have been suspected in this
process, but to date, we haven't known for sure.”
Ghafourifar's lab developed a technique allowing
researchers to watch isolated mitochondria in real
time during this process. Using chemical probes and a
novel technique called dual-wavelengths excitation
spectrophotofluorometry, they saw that after the
mitochrondria were subjected to ischemia followed by
reoxygenation, a boost of calcium occurred in the
mitochondria.
“Calcium levels went up like never before, which is
unusual, because mitochrondria typically are able to
tightly maintain a low level of calcium,” said
Ghafourifar, also an investigator in the Davis Heart
and Lung Research Institute. That glut of calcium, in
turn, triggered an enzyme to begin churning out toxic
levels of the free radical nitric oxide – much more
than the mitochondria could handle. And that excess of
nitric oxide led to the release of a mitochondrial
protein that sends the death signal to the cell.
The enzyme at work in this process is called
mitochondrial nitric oxide synthase, discovered and
reported by Ghafourifar's lab in 1997. Because
researchers don't know the cause of the calcium
increase during reoxygenation of the heart,
Ghafourifar and his colleagues have focused on the
enzyme as a therapeutic target to stop the production
of nitric oxide that leads to cell death.
“The next immediate step is finding whether we can
inhibit this enzyme so it doesn't generate excess
nitric oxide during the reoxygenation phase,”
Ghafourifar said. “We're trying to develop
experimental drugs that can be delivered at the time
of reperfusion or just before. Some seem to be
successful at selectively inhibiting the enzyme.”
The experimental therapies will soon be tested in
animal studies.
The identification of the enzyme as a target to
stop cell death could influence a range of therapeutic
options, Ghafourifar said, by applying to disease
processes characterized by cell death, or, in the case
of cancer, the refusal of cells to die when they
should.
“Cell death is involved in a variety of diseases
that don't seem to be related,” he said. “In cancer,
cells do not die. In Parkinson's and Alzheimer's
disease, cells die earlier than we want them to. If we
figure out how cell death happens, we can put up a
fight against a number of diseases.”
