Molecular Pathway, Newly Linked to PAH, May Work to Protect Lungs

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by Magdalena Kegel |

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PAH study

Both patients newly diagnosed with pulmonary arterial hypertension (PAH) and animal models of the disease show increased activity of a molecular pathway, known as NNMT-MNA (Nicotinamide N-methyltransferase and 1-methylnicotinamide), which is involved in metabolic and inflammatory reactions.

The researchers behind the study, “Activation of the nicotinamide N-methyltransferase (NNMT)-1-methylnicotinamide (MNA) pathway in pulmonary hypertension,” published in the journal Respiratory Research, believe that the increased activity might be caused by compensatory processes that aim to protect the lungs from other molecular changes.

Alterations in the NNMT-MNA pathway have mostly been explored in relation to cancer, but have also been noted in diseases as disparate as Parkinson’s and diabetes.

Interestingly, changes in this pathway can either contribute to a disease state or protect against it, and the molecular consequences of its activation apparently differ depending on which organ is involved.

So far, researchers have found that it affects metabolic processes, such as insulin resistance. Investigators at Jagiellonian University in Poland became interested in the pathway in PAH after earlier findings showing that MNA protects blood vessels. It can also protect from oxidative stress, and seems to be involved in inflammatory conditions.

Researchers first used a rat model of PAH to explore if the molecular pathway was activated. By triggering PAH development in the animals, the team noted that NNMT levels increased in both the rats’ liver and lungs as the disease developed, leading to higher plasma levels of MNA.

In patients, researchers were only able to measure MNA, which is produced by the activity of NNMT. Most patients in the study had PAH of WHO functional class III. Among 10 newly diagnosed patients, MNA levels were about three times higher than among eight control individuals. The control group was recruited among people investigated for PAH but not diagnosed with the disease, and who were, therefore, not completely healthy.

Even though the researchers could not determine precisely the organ that the MNA in patients was originating in, they suspected that it was produced in the liver, since both the rat experiments and other studies show that inflammatory reactions activate mainly liver MNA.

“Progression of pulmonary hypertension is associated with the activation of the NNMT-MNA pathway in rats and humans. Given the vasoprotective activity of exogenous MNA … the activation of the endogenous NNMT-MNA pathway may play a compensatory role in PAH,” the authors concluded.

Future studies are required to confirm this hypothesis and better understand the role of the NNMT-MNA pathway in PAH.

A Conversation With Rare Disease Advocates