March 10, 2004

Zeroing In On Stress Receptors Could
Lead To Treatment Of Heart Failure

By Sue Pondrom

A hormone that helps the body adapt to stress may provide a key to designing treatments for congestive heart failure, according to a study by researchers at the Salk Institute for Biological Studies and the University of California, San Diego (UCSD) School of Medicine.

Published in the March 9 issue of Proceedings of the National Academy of Sciences, the study establishes a firm link between a family of stress hormones called urocortins and heart disease, and may lead to new treatments for heart failure.

Congestive heart failure is an increasingly common condition among Americans, currently contributing to the deaths of more than 250,000 people annually. The ailment is marked by an impairment of heart muscle function, which eventually leads to a loss in the ability of the heart to pump blood. The known causes of congestive heart failure are multiple, and can be either acquired or inherited. In some individuals, the cause is unknown.

Wylie W. Vale, Ph.D., Helene MacLoraine Professor of Molecular Neurobiology at the Salk, Kirk L. Peterson, M.D., UCSD Edith and William Perlman Professor of Clinical Cardiology, and their colleagues found that a specific member of the urocortin family of proteins, called urocortin II, administered intravenously in a small dose, significantly enhanced heart muscle cell contractions in mice. The hormone bound to a receptor molecule called CRF2 on muscle cells. Mice bred specifically to lack the receptor showed no response to urocortin II and higher than normal blood pressure.

In addition, mice that were bred to exhibit a form of congestive heart failure were found to have a dramatic improvement in their cardiovascular function when treated with urocortin II.

“We hope that this study expands our understanding of the potent actions of urocortin II in cardiovascular physiology and points to a precise targeting of the CRF2 receptor for improved treatment of heart diseases,” Vale said.

“We believe urocortin II represents a new class of cardiovascular-active agents that may prove to have a beneficial role in the treatment of congestive heart failure,” said Peterson. “However, human urocortin is somewhat different from mouse urocortin, and further experimentation will be needed before we have a usable treatment for people.”

The researchers are continuing to work on pinpointing all of the mechanisms by which urocortin II triggers its beneficial cardiovascular effects. Further studies will take place in animals. Following their completion, human clinical trials will begin.

Additional authors of the paper were first author Tracy L. Bale, previously with the Salk Institute and currently with the University of Pennsylvania; and Mashahiko Hoshijima, Yusu Gu, Nancy Dalton and Kenneth Chien, UCSD; and Keith R. Anderson, Jeo-Fen Lee and Jean Rivier, the Salk Institute.

The study was funded by the Foundation for Research, the San Diego Foundation for Cardiovascular Research and Education, National Institute of Diabetes and Digestive and Kidney Diseases, and the Kleberg Foundation.

Media contacts:
Andrew Porterfield, Salk Institute (858) 453-4100 ext. 1340
Sue Pondrom, UCSD School of Medicine (619) 543-6163