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Because of the potential for damaging the heart with reperfusion,
many doctors and scientists have been looking for ways to
intervene at the beginning of reperfusion.
One of the approaches that scientists like Gottlieb have
taken has been to look for so-called "drugable" targets. These
are proteins or other biological molecules that are involved
in some part of a biological phenomenon like a heart attack
that might be amenable to therapy. Finding drugs that effectively
do this is another matter, but the first step is to find the
targets.
One such target, says Gottlieb, is a common protein called
cytochrome p450. This is actually a family of several dozen
metabolic enzymes that are involved in activities like removing
toxins from the body.
Cytochrome p450 proteins seem to be important for heart
attacks as well. Increases in the expression of cytochrome
p450 proteins have been correlated with some of the more traditional
risks factors for heart attacks—like high cholesterol,
smoking, and diabetes. And cytochrome p450s have the ability
to take a fatty acid that is generated during ischemia and
convert the acid to signaling molecules called eicosanoids.
"These interact with a whole host of different enzymes inside
the cell," says Gottlieb. While all the effects of the signaling
molecules are not known, what is known is that they impact
a number of different pathways involved in ion transport and
mitochondrial function and start a cascade of events that
are lethal to heart cells. The activity of cytochrome p450s
could potentially be critical to whether a cell survives or
not.
Because of this, cytochrome p450 proteins seem to be a good
drugable target, and inhibiting them might improve the survival
of heart attack victims. Gottlieb and her colleagues have
been evaluating drugs that are selective against particular
cytochrome P450 proteins to see how they perform in models
of ischemia and reperfusion.
An Exciting New Result
In a recent issue of the journal Proceedings of the National
Academy of Sciences, Gottlieb describes how a common antibiotic
called chloramphenicol, which inhibits protein synthesis in
mitochondria, can also reduce the size of a myocardial infarction
and also reduce the production of these reactive oxygen species.
Gottlieb and her colleagues report that they could not detect
an effect of chloramphenicol on protein synthesis in mitochondria,
suggesting that its protective effect was not due to this.
Instead, they propose that chloramphenicol protects the heart
by inhibiting cytochrome P450 proteins. To support this, they
demonstrated that two other cytochrome P450 inhibitors, which
were known not to inhibit protein synthesis in mitochondria,
also reduced the size of a myocardial infarction and the production
of these reactive oxygen species.
"This is a therapy that could possibly be applied after
the ischemic insult (heart attack)," says Gottlieb.
Other individuals in her laboratory are looking at questions
related to what happens inside mitochondria during apoptosis,
more specifically, how apoptosis may be relevant in the heart.
Some lab members are studying a fatty lipid molecule that
is produced by platelets and by a variety of tissue cells
called sphingosine 1-phosphate, which binds to cellular receptors
called the S1P receptors, activating them and regulating a
range of physiological functions that include cardiovascular
function and blood pressure. This work is in collaboration
with Scripps Research Professor Hugh Rosen, and is an effort
to determine if sphingosine 1-phosphate is an important pathway
in the heart and whether compounds that are chemically similar
to the lipid or drugs that bind to its receptor might play
a role in heart attacks as well.
Working with Scripps Research Institute President, Professor
Richard A. Lerner, and with Scripps Research Professor Paul
Wentworth, Jr., Gottlieb and members of her laboratory are
trying to determine if ozone is formed during myocardial ischemia
and reperfusion, and whether this dangerous allotrope of oxygen
is responsible for the damage to lipids and proteins in the
heart.
In another avenue of research, Gottlieb and her colleagues
are trying to apply a new technology called "protein transduction
domains" for delivering proteins into cells as a way of studying
signal transduction in the beating heart. A protein transduction
domain is a short sequence of amino acids that enables an
entire protein to enter the cytoplasm of a cell. She and her
colleagues are using these sequences to drag anti-apoptotic
proteins into cells to see if they can protect the heart.
Into the Sunset
If Gottlieb's days are busy with experiments, grant and
paper writing, and meetings, her evenings are even busier
with her children entering the teen years—just old enough
to have lots of places to be carted off to but not quite old
enough to drive themselves. Gottlieb gets up early every day
so that she can come home and get her children fed, shepherd
them to their various after-school activities, and get them
to bed so she can get a few hours of sleep herself in order
to be up early the next day.
This is the fun part, she admits, and she enjoys activities
like taking Tae Kwon Do with her son. "He was having so much
fun that I decided to join," she says. "Then I got hooked
on it." Soon, she says, she will test for her black belt.
Surely such hand and foot skills must also owe something
to her days back on the ranch in New Mexico. Asked if she
can still lasso a cow from atop a horse at daybreak, she laughs.
"We never did that," she says, "but I know how to vaccinate
one."
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Send comments to: jasonb@scripps.edu
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