Researchers identified two new drugs, both signaling inhibitors, that could aid in the treatment of pulmonary hypertension (PH) by altering vessel stiffness and its downstream control of metabolism. Their work also suggests that a previously unknown link exists between vessel hardening and energy production in the disease.
The study, “Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension,” was published in the Journal of Clinical Investigation.
“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, MD, PhD, director of the University of Pittsburgh Medical Center‘s Center for Pulmonary Vascular Biology and Medicine, and senior author of the study, in a university news release. “As a community, we are struggling right now to understand those origins of PH, and this study aimed to address that untapped need.”
PH, and its particularly severe subtype known as pulmonary arterial hypertension (PAH), are poorly understood vascular diseases, characterized by pro-proliferative cellular phenotypes and adverse pulmonary vascular remodeling. Alterations of the vascular extracellular matrix (ECM) are increasingly being recognized as molecular drivers of the disease.
Chan and his research team used tissues and cells from humans with PH and animal models of the disease to conduct their experiments.
The researchers discovered that the stiffening of lung vessels is an early trigger in PH, and it activates two signaling molecules, YAP and TAZ. These molecules, in turn, stimulate GLS1, a protein that controls how lung vessel cells create and utilize energy.
“The link between vessel hardening and energy production is absolutely central to this disease,” said Chan. “That discovery offers us so many new ways to design drugs tailor-made to stop PH in its tracks.”
To validate the link, researchers tested a YAP inhibitor known as verteporfin (Visudyne), an FDA-approved drug for macular degeneration. The team also tested a compound called CB-839, a GLS1 inhibitor currently in clinical trials for cancer. Researchers discovered that both drugs improved PH in a mouse model of the disease.
“We are very encouraged by these results,” said 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.”
Chan also noted that since vessel stiffness is prevalent in other conditions, such as progressing cancers, these findings may be important for diseases beyond PH.
PH results from an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, leg swelling and other symptoms. The condition affects tens of millions of people worldwide.