Distinct Gene Activity, Immune Cell Profile Found in PAH Patients

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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People with pulmonary arterial hypertension (PAH) have a distinct immune profile compared with healthy individuals, according to a new study that also found different activity levels in PAH patients of genes involved in pulmonary vascular remodeling, oxygen transport, and blood cell development.

In fact, more than 1,200 genes were identified as having different activity levels in PAH patients relative to individuals without the chronic progressive disease.

“These identified genes and these immune cells probably have precise regulatory relationships in the development of PAH,” the researchers wrote, adding that these “key genes” might represent “underlying targets for therapeutic makers.”

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The study, “Integrated bioinformatics analysis reveals marker genes and immune infiltration for pulmonary arterial hypertension,” was published in Scientific Reports.

PAH is characterized by the narrowing of the pulmonary arteries, which carry blood from the right side of the heart to the lungs. This arterial narrowing restricts blood and oxygen flow, and raises blood pressure (hypertension). It is the result of pulmonary vascular remodeling, a process that involves the uncontrolled growth of smooth muscle cells, which progressively thickens the arterial walls.

While a comprehensive understanding of the disease’s mechanisms is lacking, genetic factors are thought to play an important role in the development of pulmonary hypertension in all of its forms. Researchers say a better understanding of these factors may yield more promising therapeutic approaches. To date, there is no cure for PAH; a variety of therapies are available, but they only help to ease the disease’s symptoms.

New advances in bioinformatics — the application of computational tools to interpret biological information — have now enabled the large-scale analysis of genetic sequencing data. The results are now being used by scientists to search for genetic factors associated with specific diseases.

Here, a trio of researchers in China examined gene activity data from blood samples of 32 PAH patients and 29 healthy people, who served as controls. The data were obtained from three large gene activity databases in the country.

Identifying different gene activity in PAH

Results showed that the activity of 1,277 genes was significantly distinct between the PAH and control groups. More than two-thirds (68.4%) of these so-called differentially-expressed genes (DEGs) were less active in patients, while the remaining 31.6% were overly active.

The scientists noted that many of these genes were found to be involved in blood and immune cell function and in TGF-beta signaling, which has been implicated in PAH.

A deeper analysis revealed 10 hub genes that seemed to have the strongest association with PAH: SLC4A1, AHSP, ALAS2, CA1, HBD, SNCA, HBM, SELENBP1, SERPINE1, and ITGA2B. 

These genes were mostly involved in processes such as oxygen and carbon dioxide transport, red blood cell development, and blood clotting. They also were part of the process of hydrogen peroxide breakdown, which results in water and oxygen.

“It is speculated that these significant DEGs theoretically lead to the occurrence and progression of PAH,” the researchers wrote.

The team also identified a handful of proteins, known as transcription factors, that likely regulate the activity of the identified DEGs. These transcription factors may thereby contribute to “the development and progression of PAH,” the researchers wrote.

Overall, the findings suggest that targeting these genes or transcription factors may help prevent pulmonary vascular remodeling and ease PAH.

Because inflammation also is thought to be a significant contributor to PAH, the team also examined blood levels of several different immune cell types.

Compared with controls, people with PAH showed higher levels of multiple types of immune cells in their blood, including activated natural killer cells, monocytes, activated memory T-cells, and mast cells. In turn, inactivated T-cells were lower in patients than in healthy individuals.

“Since a large number of immune cells are clearly changed in PAH, although it is not clear how the immune system affects vascular remodeling, it can be conjectured that immune system goes a long way in this pathological process,” the researchers wrote.

“Further experiments on immune cells can identify targets to perfect immuno-modulatory therapy for PAH patients,” they added.

More work needs to be done to learn about the relationship between gene activity changes, immune cells, and PAH, the researchers said.

“Key genes and [transcription factors] are tightly related to the occurrence of PAH,” they concluded, adding that now “it is necessary to explore the specific mechanism using some animal and cell experiments.”