A team of researchers at the University of Pittsburg and UPMC (University of Pittsburg Medical Center) identified two medications — one already approved and one in clinical testing — that might work to treat pulmonary hypertension (PH) by altering vessel stiffness and its effect on energy metabolism in cells.
Neither drug, both signaling inhibitors, were designed as therapies for PH.
The team, led by Dr. Stephen Y. Chan, director of the UPMC Center for Pulmonary Vascular Biology and Medicine at the Vascular Medicine Institute at Pittsburg, discovered that the stiffening and hardening of lung arteries that causes PH triggers the activation of two signaling molecules, called YAP and TAZ. These molecules, in turn, activate a protein called GLS1, which plays a role in energy production and energy usage in the cells of lung vessels.
The link between vessel hardening and energy metabolism was previously unknown. “[I]t is absolutely central to this disease,” said Chan in a press release. “That discovery offers us so many new ways to design drugs tailor-made to stop PH in its tracks.”
He added: “There is always more work to be done, but we feel this represents a significant milestone in our quest to cure this disease.”
These new findings could also be relevant for PH caused by the human immunodeficiency virus (HIV) infection, a form of the disease where the underlying molecular mechanisms have been unknown for decades.
To confirm that YAP and TAZ, and their downstream GLS1, are central to the development of the disease, researchers used a compound called verteporfin, which inhibits YAP, and another compound called CB-839, which inhibits GLS1. Researchers saw that both compounds strongly improved PH in a mouse model of the disease.
Verteporfin is a medication approved by the U.S. Food and Drug Administration (FDA) to treat macular degeneration, and CB-839 is currently in clinical trials as a potential cancer treatment.
Scientists are now working on repurposing these drugs for the treatment of PH. This could mean that years of testing required when developing drugs might not be necessary, because these potential treatments are not being developed from scratch.
The study, “Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension,” was published in The Journal of Clinical Investigation.