University of Pittsburgh
Enzyme May Play Key Role in Pulmonary Arterial Hypertension
We will study the role of nitrate as a treatment for pulmonary arterial hypertension (PAH). Many features of PAH are associated with dysfunctional signaling mechanisms of nitric oxide (NO). Nitrite is a source of NO that acts in low-oxygen conditions. Several mechanisms for how nitrite is converted to NO have been investigated, yet no conclusive data points to a single enzyme as an indispensable component. We will focus on an enzyme called mARC-2, to see if it plays a key role in converting nitrite to NO, and whether it can be enhanced as a specific therapy for PAH.
Update: Pulmonary hypertension can occur when the arteries in the lungs narrow and thicken, slowing the flow of blood through the pulmonary arteries to the lungs. We have demonstrated that mARC-2 nitrite conversion to NO is regulated by oxygen, suggesting that the low oxygen environment of PAH would be the ideal environment for this enzyme to function and generate NO-based widening of the blood vessels. We have confirmed that human blood vessel cells can use nitrite to produce cGMP, an important molecule to widening of the blood vessels. We have also detected differences in mARC-2 levels in humans with lung disease. We are utilizing genetically modified mice that do not have the mARC2 enzyme, to determine if deleting mARC-2 in mice stops transformation of nitrite into NO.