EMBARGOED by NEW ENGLAND JOURNAL OF MEDICINE
For 5 pm EST Wednesday, February 5, 2003

UCSD Researchers Identify Gene Pathway
Causing Pulmonary Hypertension

Researchers at the University of California, San Diego (UCSD) School of Medicine have identified an over-active gene and the molecular events it triggers to cause acquired cases of pulmonary hypertension, a form of high blood pressure in the lungs that kills about one percent of the population each year.

The findings, published in the February 6, 2003 issue of the New England Journal of Medicine, offer the first specific molecular targets for development of new therapies.

"Although a small subset of patients benefit from surgery to remove blood clots from the lungs, currently the only treatment for most types of pulmonary hypertension is lung transplantation," said the study's senior author Patricia Thistlethwaite, M.D., Ph.D., an assistant professor in the UCSD Division of Cardiothoracic Surgery.

The researchers found that a gene called angiopoietin-1, which is normally involved in smooth-muscle growth in newly developing embryonic blood vessels, somehow gets inappropriately turned on in adulthood. As angiopoietin-1 aberrantly over-expresses itself, it initiates a molecular chain of events that causes muscle cell proliferation within the lining of the lung's blood vessels. As the vessel wall thickness grows, the small lung arteries become progressively narrowed and blocked.

Almost all patients with pulmonary hypertension acquire the disease from diverse causes such as congenital heart defects, autoimmune disease, left-sided heart failure, blood clots in the lungs, drug interactions or vascular diseases. A handful of patients inherit a rare form of the disease from a mutation in a gene called bone morphogenetic protein receptor type2 (BMPR2).

"We wondered whether a common molecular mechanism underlies all the different causes of pulmonary hypertension as well as the inherited form," Thistlethwaite said.

The investigators reasoned that since angiopoietin-1 was involved in embryonic smooth-muscle development, an aberrant turn-on of this gene might cause the over-growth of muscle tissue in adults. During an 18 month period, the team obtained lung biopsies from 42 pulmonary hypertension patients who had acquired pulmonary hypertension from a variety of causes. For comparative purposes, they also obtained biopsies from 19 individuals without pulmonary hypertension, who were undergoing lung surgery.

Using sophisticated laboratory tests on the lung tissue, the scientists found that angiopoietin-1 attached itself to a receptor (or docking protein) called TIE2, which is only located in the lining of blood vessels. In turn, the angiopoietin-1/TIE2 duo caused the down-regulation, or work slow-down, of another gene called bone morphogenetic protein receptor type1 (BMPR1). The result was the muscle build-up characteristic of pulmonary hypertension.

"Researchers have known for years that BMPR1 and BMPR2 work together on the cell surface to stimulate intracellular signaling," said Thistlethwaite. "This means that our findings show a link between the inherited form of pulmonary hypertension, caused by a BMPR2 mutation, and the non-familial, acquired form, caused by the angiopoietin-1, TIE2, BMPR1 molecular pathway."

Currently, the Thistlethwaite team is working on potential inhibitors of angiopoitin-1, to see if they can stop pulmonary hypertension in rodent models.

The study was funded by the Charles B. Wang Foundation and grants from the National Institutes of Health. Additional authors of the paper were Lingling Du, M.D.; Christopher C. Sullivan, M.S.; Danny Chu, M.D.; Augustine J. Cho, B.A.; Masakuni Kido, M.D., and Stuart W. Jamieson, M.D., FRCS, UCSD Division of Cardiothoracic Surgery; Paul L. Wolf, M.D., UCSD and the San Diego VA Healthcare System; Jason X.-J. Yuan, M.D., Ph.D., UCSD Pulmonary and Critical Care Medicine; and Reena Deutsch, Ph.D., UCSD Biostatistics.

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News media contact:
Sue Pondrom
619-543-6163
spondrom@ucsd.edu

UCSD Health Sciences Communications HealthBeat: http://health.ucsd.edu/news/