A new molecular mechanism in the development of World Health Organization (WHO) Group 1 pulmonary hypertension (PH) – pulmonary arterial hypertension (PAH) – has been discovered by investigators from the Brigham and Women’s Hospital, through work funded in part by the Pulmonary Hypertension Association (PHA). NEDD9, a protein that was discovered in 1992 and has been studied in cancer research, was reported this week in an article appearing in Science Translational Medicine as important in the development of PAH.

PAH is a rare, progressive disease characterized by high blood pressure in the arteries of the lungs, as well as increased resistance to blood flow through the lungs. Scientists have long described many changes in the blood vessels (including lung arteries that are thicker than normal, narrowed or even blocked) of the lungs of people with PAH, leading to this increased pressure. In addition to an overgrowth of cells in the lung arteries, scientists also have found increased signs of fibrosis, or scarring, which can further stiffen the blood vessels.

Bradley Maron, M.D., a grantee from the PHA research program, and his colleagues at the Brigham and Women’s Hospital in Boston, were interested in learning more about the cause of this fibrosis in patients with PAH. Using network medicine, a research method that attempts to identify previously unknown connections between the many genes and proteins in the body, Dr. Maron and his colleagues discovered a connection between the cancer protein NEDD9 and fibrosis in the blood vessels of the lungs of PAH patients. The team discovered a specific area of the protein (an amino acid) that controls the fibrotic effect of NEDD9, as well as the contribution of cells in the pulmonary arteries, in the innermost layer of the pulmonary artery, the endothelium, that was not previously known to contribute to fibrosis.

“Our work identifies as a novel molecular target to prevent fibrosis in lung arteries, which can lead to early right-sided heart failure and death,” said Dr. Maron. “Our data provide an alternative mechanism that may account for the variability in fibrosis observed across subgroups of patients with PAH.”

In their paper, Dr. Maron and his colleagues note that this discovery offers the potential to investigate new therapies for PAH in new pathways not previously researched. However, further research will be required to learn more about the relationship between NEDD9, fibrosis and PAH before this type of application.

Funding for this work was provided by PHA, the National Institutes of Health, the American Heart Association, the Cardiovascular Medical Research and Education Fund (CMREF), the Klarman Foundation at Brigham and Women’s Hospital and the Systemic Sclerosis Foundation.