An Irish researcher in the US has come up with an unusual new ally in thefight against human heart disease - the zebrafish. Dick Ahlstrom reports

What do the zebrafish and human heart disease have in common? Quite a lot, according to a research team at the University of Pennsylvania in Philadelphia.

The scientists, headed by an Irishman, found that the zebrafish produces two proteins very similar to human proteins that have important connections to heart disease. This makes the zebrafish important to future studies of drugs that can reduce the risk of heart attack in humans.

Prof Garret FitzGerald, originally from Dublin, is chairman of the department of pharmacology at Penn and director of the Penn Centre for Experimental Therapeutics. He, lead author Dr Tilo Grosser and colleagues published their findings about the zebrafish this month in the Proceedings of the National Academy of Sciences.

These are the result of many years of work by FitzGerald with two key human enzymes, cyclooxygenases, known as COX-1 and COX-2. They play a role in a variety of ailments, including cardiovascular disease, some types of cancer and arthritis.

The proteins are like the two ends of a seesaw, performing a balancing act that increases or decreases the stickiness of blood and the diameter of the blood vessels. They also play a role in inflammation.

COX-1 is found in platelets, the blood cells that form clots. It produces a substance that makes platelets sticky and causes blood vessels to constrict. These are useful responses to help close a cut, but become life-threatening as a prelude to heart attack or stroke.

COX-2 is expressed in blood vessels and produces a substance that opens up the vessels and blocks the activation of platelets.

These two enzymes are the targets of various drug therapies. Aspirin blocks the action of COX-1, can thin blood and is a painkiller useful in inflammation. It can also, unfortunately, cause stomach irritation that can lead to ulcers.

Drugs that block COX-2 can decrease the pain associated with inflammation and are therefore often used to control the pain of arthritis. They do so without causing stomach irritation, which is an advantage, but it remains unclear whether tampering with the balance between the two COX enzymes could cause problems.

Last April, FitzGerald, lead author Dr Yan Cheng and colleagues at Penn published an explanation of the interaction between COX-1 and COX-2 in the journal, Science. They wanted to investigate "the interplay of the two COX products in the cardiovascular system", FitzGerald explains.

They found that the COX-2 product, prostacyclin, played a vital role in restraining the harmful cardiovascular effects of the COX-1 product, thromboxane. The team used mice bred so that their systems couldn't use prostacyclin, imitating the effect of a COX-2 inhibitor. The researchers discovered that the mice had a greatly exaggerated response to injury and activation of their platelets, leaving them at greater risk of unwanted blood clots.

ENTER the zebrafish. The fish produce enzymes that match the two COX enzymes, and the new research shows that they respond to drugs in a way similar to the human enzymes.

"We have learned a great deal about how the COX enzymes and their inhibitors work from mouse models of COX gene inactivation. However, these systems have their limitations," FitzGerald says. "The zebrafish promises to play a complementary role in which both biology and the role of drugs can be investigated."

The fish are likely to have a key part in the identification of drugs useful for the regulation of the COX enzymes, the researchers believe.

"The zebrafish has particular advantages for the study of drug action," says the lead author in the zebrafish paper, Dr Grosser. "Their embryos are translucent, so we can study the pattern of gene expression during development, as well as in the adult.

"The near-completion of the zebrafish genome project allows us to hunt for relatives of human genes of interest. Then we can manipulate them and see how they function."

While any new drug will still have to go through detailed safety tests, at least researchers will have good solid clues about their likely effects and whether they are suitable to the job.

This could mean safer, more effective pain control and a reduction in heart attack risk for patients.