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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"This is a therapy that could possibly be applied after the ischemic insult (heart attack)."

—Roberta Gottlieb