Science Editor

"In the cardiology field, many people believe that oxidative stress is very important for both injury and growth," Junichi Sadoshima told BioWorld Today. "But not many targets of oxidative stress have been found."

In a paper in the June 13, 2008, issue of Cell, Sadoshima, who is professor and vice chair in the department of cell biology and molecular medicine at the UMDNJ-New Jersey Medical School and associate director of its Cardiovascular Research Institute, along with his colleagues at UMDNJ and the University of Cincinnati, identified the target of oxidative stress in one form of injury, cardiac hypertrophy.

In a nutshell, Sadoshima said, scientists found that "oxidative stress targets histone deacetylases, and thioredoxin can protect the heart."

Cardiac hypertrophy, the thickening of the heart wall, starts out as an adaptive response - most commonly due to high blood pressure or heart valve stenosis - but turns problematic. Such growth ultimately increases cell death, and heart tissue does not regenerate. Ultimately, cardiac hypertrophy is one of the most common causes of heart failure in the U.S.

The scientists first performed a microarray analysis to search for genes activated by the antioxidant protein thioredoxin-1, and found that among those genes is one - DnaJb5 - that is up-regulated by thioredoxin and goes on to form a complex with thioredoxin and a third protein.

That complex suppressed the activity of transcription factors that are active under conditions that normally lead to hypertrophy, and it prevented heart muscle cells from growing.

The thioredoxin-DnaJb5 complex appeared to work by reducing several amino acids on HDAC4, a histone deacetylase that is expressed in heart muscle cells.

That prevented HDAC4 from being transported from the nucleus into the cytoplasm.

Since histone deacetylases and their counterpoints, histone acetyltransferases, control gene expression by modifying chromosomal structure to make genes either more or less accessible to the cell's transcription machinery, they need to be located in the nucleus to interact with the chromosomes.

When HDAC4 is reduced, it can remain in the nucleus and inhibit transcription factors that usually respond to hypertrophic stimuli.

Somewhat surprisingly, oxidation appeared to trump phosphorylation - the best-known form of HDAC control - when it came to determining the location of HDAC4. Mutant HDAC4s that were both phosphorylated - which should be a ticket to the nucleus - and reduced rather than oxidated - which would favor their staying put - tended to remain in the nucleus.

The authors noted in their paper that oxidation occurs "more rapidly than phosphorylation after hypertrophic stimulation. Those findings suggested that nuclear export of HDAC4 may be biphasic, with redox regulation mediating the early phase of nuclear export."

The mechanism appears to be specific to problematic forms of hypertrophy - as Sadoshima pointed out, athletes also have enlarged hearts, but in the case of an athlete, when the heart muscle enlarges, its function increases. In hypertension or ischemia patients, however, function decreases as the muscle enlarges.

Sadoshima concluded that targeting thioredoxin "might be a novel way" of approaching cardiac hypertrophy. However, as a first step, he and his colleagues need to figure out a way to deliver thioredoxin directly to heart cells.

Bloodstream delivery is not feasible - ironically, because thioredoxin is oxidized too rapidly in the blood to do any good.