UM Researchers Find Molecule Regulates Cardiac Hypertrophy

9/12/2008

Researchers at the University of Miami Miller School of Medicine, led by Nanette Bishopric, M.D., have made a discovery that identifies a key molecule responsible for excessive growth of the heart muscle, or hypertrophy, which may lead to heart failure. The findings could lead to new preventive therapies for adults and children.

Nanette Bishopric, M.D.

The molecule, acetyltransferase p300, is essential for cardiac development. Using mouse models, the research team found that excess amounts of p300 in the heart lead to a corresponding degree of hypertrophy.  Reducing p300 resulted in less hypertrophy in response to stress such as high blood pressure, and too much p300 led to spontaneous hypertrophy and eventually to heart failure and death.

“The data shows that p300 is responsible for driving hypertrophy after pressure overload and for driving the subsequent heart failure," said Bishopric, professor of medicine, pediatrics and pharmacology at the Miller School. The findings, published in August in the prestigious journal Circulation, suggest that regulating p300 could protect against stress-induced hypertrophy and forestall the development of heart failure.

The study also shows a narrow window between adequate and inadequate levels of p300. "No one has ever shown this rigid dose dependence for a molecule involved in hypertrophy," says Bishopric. "Overexpressing p300 by two-fold gives two times the growth."

Bishopric and her team found that as part of normal heart functioning, p300 levels spike in response to acute stress, temporarily stimulating heart growth and protecting it from damage. Under chronic stress, however, sustained up-regulation of levels of p300 leads to heart failure.

The findings also have implications for heart failure in children. "Dr. Bishopric’s paper is a seminal work in the field," says Steven E. Lipshultz, M.D., chairman of pediatrics and associate executive dean for child health at the Miller School, who has published research on hypertrophy of the heart in children.

“In children we have studied, excessive heart muscle growth is a strongly significant predictor of increased risk of early death, and excessive hypertrophy is independent of other factors in predicting early death," Lipshultz said.  "In the special populations of kids we have followed, those who either have too much or too little hypertrophy of the heart muscle are at greater risk for worse outcomes."

Past studies have shown that certain natural remedies, including cashews, rosehips and curry powder, can inhibit p300, but Bishopric believes this new UM research will lead to more effective, potent therapies.

“We’re hoping to work with experts in drug design to develop new potential drug candidates for targeting p300," said Bishopric. "There may be other therapies more selective and easier to use than what’s currently available."