AARDC3 gene may be biomarker, treatment target in CTEPH
Gene active in CTEPH patients implicated in inflammation, cell growth
The ARRDC3 gene — implicated in inflammation and cell growth — may be a ferroptosis-related biomarker and treatment target in chronic thromboembolic pulmonary hypertension (CTEPH), according to a new study.
Ferroptosis is an iron-dependent type of cell death involved in the damage of lung blood vessels and in lung diseases.
“Our study might provide new insights into the prevention, monitoring and potential therapeutic intervention for CTEPH,” the researchers wrote.
Titled “Identification of Ferroptosis-related potential biomarkers and immunocyte characteristics in Chronic Thromboembolic Pulmonary Hypertension via bioinformatics analysis,” the study was published in the journal BMC Cardiovascular Disorders.
Of 4 genes, only ARRDC3 seen as potential CTEPH biomarker, treatment target
CTEPH is a type of pulmonary hypertension, a disease associated with abnormally high pressure in the pulmonary arteries, caused by the formation of blood clots.
The condition is difficult to diagnose in its early stages, and no biomarkers have been identified to predict its severity and prognosis.
“As a result, it is crucial to explore more valuable genetic biomarkers for the potential etiology [causes] and therapeutic targets of CTEPH,” the researchers wrote.
Several studies have recently focused on discovering biomarkers of ferroptosis. The process leads to damage in pulmonary blood vessels through oxidative damage — when toxic reactive oxygen species outweigh the body’s antioxidant defenses — and to shrinkage of mitochondria, the chief cellular structures in energy production.
“However, it remains a great challenge to explore the reliable gene biomarkers and specific regulatory details associated with ferroptosis in CTEPH,” the researchers wrote.
To learn more, researchers from China turned to bioinformatics, or the use of computer technology to collect, store, and analyze biological data. The team was able to screen changes in genes related to ferroptosis, and explore how they can affect the immune environment in pulmonary vessels. Immune cells contribute to CTEPH by releasing inflammatory molecules and being involved in the formation of blood clots.
Using the GSE130391 database, the researchers extracted 676 genes whose expression, or activity, was different when comparing CTEPH with controls.
In total, 17 genes related to ferroptosis were differentially expressed. These genes were associated with inflammation, cell growth, cell death, balance of iron, and removal of damaged mitochondria, which are the powerhouses of cells.
Surprisingly, according to the researchers, there were 17 ferroptosis-related biomarkers implicated in immune processes.
“Collectively, these evidences indicated that 17 intersection genes mentioned may play an important role in the [disease mechanisms] of CTEPH by participating in the regulation of immune cells and cytokines,” the researchers wrote. Cytokines are small proteins involved in cell signaling, cell-to-cell communication, and immune responses.
The researchers then selected the genes most suitable to be biomarkers for CTEPH. These included the ARRDC3, HMOX1, BRD4, and YWHAE genes, which play a role in inflammation, cell growth, and cell division, among other processes.
“In this study, our results indicated that [these genes] were involved in CTEPH progress possibly through regulating inflammatory, vascular cell proliferation, smooth muscle cell invasion and apoptosis,” the researchers wrote. Apoptosis is a type of programmed cell death, as opposed to cell death caused by injury.
When the scientists used the GSE188938 dataset used to identify markers and signaling pathways involved in CTEPH, only the ARRDC3 gene was significantly more active in CTEPH patients than in controls.
“These results indicated that ARRDC3 may be the most important hub gene of CTEPH and a potential therapeutic target,” the researchers wrote.
Further analysis revealed a reduced infiltration of eosinophils and neutrophils in CTEPH samples than in controls. These immune cells have been involved in disease mechanisms leading to CTEPH.
Higher activity of ARRDC3 significantly correlated with more infiltration of immune T follicular helper cells and less of neutrophils.
These results indicated that ARRDC3 may be the most important hub gene of CTEPH and a potential therapeutic target.
Overall, this indicates that “ARRDC3 might [be] a potential and promising ferroptosis-related biomarker for CTEPH treatment,” the researchers wrote.
Study limitations included the sample size of the used datasets, variable clinical parameters of CTEPH patients, and lack of disease severity grading, the team noted.
“Further experimental verification are warranted to confirm the effects and functional correlation of the identified genes and pathways, and provide more accurate characterization of immune cell populations in CTEPH,” the researchers wrote.