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Mitochondria send death signal to cardiac cells, study shows
Date:11/8/2007

'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 therapi
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Contact: Emily Caldwell
emily.caldwell@osumc.edu
614-293-3737
Ohio State University
Source:Eurekalert

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