Researchers Discover Existing Drugs May Prevent Enlarged Hearts

April 17, 1998

DALLAS -- April 17, 1998 -- Using two drugs already available, researchers at UT Southwestern Medical Center at Dallas may have found a cure for a condition that puts 5 million Americans at risk for sudden death -- an enlarged heart, or cardiac hypertrophy.

In groundbreaking research Dr. Eric Olson, chairman of molecular biology and oncology, and his colleagues discovered a molecular pathway that leads to heart enlargement and have found a way to block that pathway using an immunosuppressant drug already approved by the Food and Drug Administration, although not for that condition. Their study, published in the April 17 issue of Cell, was done in mice whose progression from cardiac hypertrophy to heart failure to death mirrored humans'.

"Cardiac hypertrophy is the response of the heart to all sorts of damage, like hypertension or heart attacks or endocrine disorders or mutations. What the heart does is try to compensate for that damage by increasing its size to achieve greater cardiac output," said Olson.

Initially this is beneficial, but ultimately the heart may enlarge too much, causing congestive heart failure that can lead to sudden death. Half of cardiac hypertrophy patients die from the condition.

Olson and his research team showed that cardiac hypertrophy is controlled by a single protein, calcineurin, which acts as a gatekeeper to the cell¢s nucleus, the control room where specific molecules regulate gene function. When stimulated by a sustained increase in the cell¢s calcium level, calcineurin activates its target protein, NFAT3, which then enters the nucleus and turns on the genes that cause heart enlargement.

The researchers genetically engineered two strains of mice to test their hypotheses. One strain continually expressed activated calcineurin in heart muscle cells, which allowed activated NFAT3 to enter the nucleus and start the hypertrophic response. By day 18 of life, the mice's hearts had enlarged to two to three times normal size, proving that activated calcineurin is sufficient to induce cardiac hypertrophy. At the least sign of stress the mice died. The appearance of their hearts mirrored those of humans?dilated ventricular chambers indicative of heart failure.

To confirm that activated NFAT3 alone could signal the hypertrophic response, a second strain of transgenic mice was designed to express activated NFAT3 in heart muscle cells. These transgenic mice also had enlarged hearts.

"Since calcineurin is the key signal for the hypertrophic response cascade, we reasoned that cardiac hypertrophy could be treated with the immunsuppressants cyclosporine A and FK506," said Olson, director of the Nancy B. and Jake L. Hamon Center for Basic Research in Cancer and holder of the Nancy B. and Jake L. Hamon Distinguished Chair in Basic Cancer Research. Cyclosporine A and FK506 are prescribed to prevent transplanted organ rejection and are known to inhibit calcineurin.

Using calcineurin transgenic mice, the investigators were able to prevent cardiac hypertrophy with cyclosporine A or FK506. After 16 days of treatment, the hearts of the cyclosporine-treated transgenic mice were comparable in size and morphology to those of normal mice; the untreated transgenic mice had hearts nearly threefold larger.

Other UT Southwestern authors of the study were former student Dr. Jeffery Molkentin; Jianrong Lu and Christopher Antros, graduate student research assistants in molecular biology and oncology; and Dr. James Richardson, associate professor of pathology. Dr. Jeffrey Robbins of Children¢s Hospital Medical Center in Cincinnati and Dr. Steven Grant of the University of North Texas Health Science Center in Fort Worth also participated in the study.

The research was funded in part by the National Institutes of Health.

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