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New Understanding of Pulmonary Hypertension Leads to Promising Drug Targets
  • USA - English


News provided by

UPMC

Aug 22, 2016, 16:00 ET

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The link between vessel hardening and energy production is absolutely central to this disease. That discovery offers us so many new ways to design drugs tailor-made to stop pulmonary hypertension in its tracks.

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Pittsburgh, PA (PRWEB) August 22, 2016 -- A groundbreaking new study led by researchers from the University of Pittsburgh and UPMC has identified a new group of compounds that could have robust effects in treating pulmonary hypertension (PH), an enigmatic but sometimes fatal disease of the blood vessels of the lungs that currently has no cure. The findings, which were published today in the Journal of Clinical Investigation, highlight the use of these drugs to alter vessel stiffness and its downstream control of metabolism, a link previously unknown for people suffering from the progressive disease.

“If we aim to cure this disease, the next set of medications and treatments should be those that target the origin at the molecular level,” said Stephen Y. Chan, M.D., Ph.D., director of the UPMC Center for Pulmonary Vascular Biology and Medicine at the Vascular Medicine Institute at Pitt, and senior author of the study. “As a community, we are struggling right now to understand those origins of PH, and this study aimed to address that untapped need.”

Affecting tens of millions of people worldwide, PH is high blood pressure in the arteries in the lungs, which makes it difficult for blood to flow from the heart to the lungs. Symptoms of the disease, which can lead to heart failure, include shortness of breath, fatigue and chest pain; and, in its early stages, might not be noticeable for months or even years. Often a life-threatening condition, it becomes progressively worse, making early and accurate diagnosis important to allow treatments that extend and improve the quality of life for many patients.

To make these discoveries, Dr. Chan and his colleagues used a comprehensive array of tools derived from cells and tissues of animal and humans with PH. Notably, these findings also were relevant to PH caused by human immunodeficiency virus (HIV) infection—a particularly mysterious form of this disease where the underlying molecular processes have remained unknown for decades.

Dr. Chan’s team found that stiffening or hardening of the vessels in the lung is an early event in PH that triggers the activation of two critical signaling molecules called YAP and TAZ. These molecules in turn activate a protein called GLS1, which controls how cells in the vessel produce and use energy.

“The link between vessel hardening and energy production is absolutely central to this disease,” said Dr. Chan. “That discovery offers us so many new ways to design drugs tailor-made to stop PH in its tracks.”

As proof-of-concept, Dr. Chan’s team tested both the YAP inhibitor verteporfin, a Food and Drug Administration-approved medication for macular degeneration, and a GLS1 inhibitor called CB-839, which is in clinical trials for cancer. They found that both of these compounds displayed robust effects in improving PH in a rodent model of disease.

“We are very encouraged by these results,” said Dr. Chan. “We are working to repurpose these drugs for treatment of human PH, which now can include long-neglected disease types such as HIV-related conditions and others. We hope that we can do so without the delay of decades that often happens when developing new compounds from scratch.”

Given that vessel stiffness is prevalent in other diseases—including cancer progression—these results also may be important beyond PH, noted Dr. Chan.

“There is always more work to be done,” he said. “But, we feel this represents a significant milestone in our quest to cure this disease.”

# # #

About the University of Pittsburgh: A nonsectarian, coeducational, state-related, public research university founded in 1787, the University of Pittsburgh (Pitt) is a member of the prestigious by-invitation-only Association of American Universities and internationally renowned as a leading center of learning and research in the arts, sciences, humanities, professions, and health sciences. Comprising a Pittsburgh campus, which is home to 16 undergraduate, graduate, and professional schools, and four Western Pennsylvania regional campuses, Pitt offers nearly 400 distinct degree programs and confers more than 7,500 degrees annually. Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1998, and is ranked among the top 10 American research universities nationally in terms of total federal science and engineering research and development obligations. For more information, visit http://www.pitt.edu.

About UPMC
A world-renowned health care provider and insurer, Pittsburgh-based UPMC is inventing new models of patient-centered, cost-effective, accountable care. It provides more than $892 million a year in benefits to its communities, including more care to the region’s most vulnerable citizens than any other health care institution. The largest nongovernmental employer in Pennsylvania, UPMC integrates 60,000 employees, more than 20 hospitals, more than 500 doctors’ offices and outpatient sites, and a more than 2.9 million-member Insurance Services Division, the largest medical and behavioral health services insurer in western Pennsylvania. Affiliated with the University of Pittsburgh Schools of the Health Sciences, UPMC ranks No. 12 in the prestigious U.S. News & World Report annual Honor Roll of America’s Best Hospitals. UPMC Enterprises functions as the innovation and commercialization arm of UPMC while UPMC International provides hands-on health care and management services with partners in 12 countries on four continents. For more information, go to UPMC.com.

http://www.upmc.com/media

Lawerence Synett, UPMC, +1 412-647-9816, [email protected]

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