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New understanding of pulmonary hypertension leads to promising drug targets

Date:
August 22, 2016
Source:
University of Pittsburgh Schools of the Health Sciences
Summary:
New compounds that could have robust effects in treating pulmonary hypertension have been identified by researchers. Pulmonary hypertension is an enigmatic but sometimes fatal disease of the blood vessels of the lungs that currently has no cure.
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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 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."


Story Source:

Materials provided by University of Pittsburgh Schools of the Health Sciences. Note: Content may be edited for style and length.


Journal Reference:

  1. Thomas Bertero, William M. Oldham, Katherine A. Cottrill, Sabrina Pisano, Rebecca R. Vanderpool, Qiujun Yu, Jingsi Zhao, Yiyin Tai, Ying Tang, Ying-Yi Zhang, Sofiya Rehman, Masataka Sugahara, Zhi Qi, John Gorcsan, Sara O. Vargas, Rajan Saggar, Rajeev Saggar, W. Dean Wallace, David J. Ross, Kathleen J. Haley, Aaron B. Waxman, Victoria N. Parikh, Teresa De Marco, Priscilla Y. Hsue, Alison Morris, Marc A. Simon, Karen A. Norris, Cedric Gaggioli, Joseph Loscalzo, Joshua Fessel, Stephen Y. Chan. Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. Journal of Clinical Investigation, 2016; DOI: 10.1172/JCI86387

Cite This Page:

University of Pittsburgh Schools of the Health Sciences. "New understanding of pulmonary hypertension leads to promising drug targets." ScienceDaily. ScienceDaily, 22 August 2016. <www.sciencedaily.com/releases/2016/08/160822174057.htm>.
University of Pittsburgh Schools of the Health Sciences. (2016, August 22). New understanding of pulmonary hypertension leads to promising drug targets. ScienceDaily. Retrieved May 23, 2017 from www.sciencedaily.com/releases/2016/08/160822174057.htm
University of Pittsburgh Schools of the Health Sciences. "New understanding of pulmonary hypertension leads to promising drug targets." ScienceDaily. www.sciencedaily.com/releases/2016/08/160822174057.htm (accessed May 23, 2017).

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