Long noncoding RNA may be new biomarker for PAH: Study

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by Andrea Lobo |

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A long noncoding RNA molecule (lncRNA) — a long segment of RNA that regulates protein production in the body — may activate or inhibit genes associated with pulmonary arterial hypertension (PAH), according to researchers in China.

In their study, a lncRNA was found at higher levels in children with this rare type of pulmonary hypertension (PH).

LncRNAs are suggested to work by interacting with and blocking microRNAs, small segments of RNA that prevent protein production by binding to messenger RNA (mRNA). mRNA is the intermediate molecule that carries the instructions to produce proteins from DNA.

“It is expected that lncRNA-TCONS_00008552 could become a new therapeutic target and biomarker for PAH,” the scientists wrote.

The study, “lncRNA-TCONS_00008552 expression in patients with pulmonary arterial hypertension due to congenital heart disease,” was published in the journal PLOS One.

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Long Noncoding RNAs May Have Role in PH Onset, Rat Study Finds

Study IDs potential new biomarker for PAH

PAH is characterized by the narrowing of pulmonary arteries, the blood vessels that carry blood to the lungs. This causes high blood pressure — hypertension — and makes the heart work harder to pump blood.

Multiple factors contribute to PAH development, making it key to identify new molecular markers for early diagnosis, prognosis, and treatment.

The abnormal activity of genes linked with changes in lncRNA levels has been associated with the occurrence of cardiovascular and pulmonary diseases.

Several lncRNAs were shown to be differentially expressed — meaning they were found at different levels — in PAH, making them potentially useful. However, “the role of lncRNAs in PAH is still in the preliminary stages of research and the specific mechanism remains unelucidated,” the scientists wrote.

In this investigation, the researchers compared the expression of lncRNAS and mRNAs in children with severe PAH secondary to ventricular septal defect (VSD), and those with VSD but without PAH. VSD is a birth defect of the heart in which there is a hole in the wall that divides the two lower chambers (ventricles) and keeps oxygen-rich blood from mixing with oxygen-poor blood.

The study included eight children, ages 6-10, who were admitted to a hospital in China in 2022. Four of the children had moderate or severe PAH secondary to VSD, and four had VSD without PAH.

Patients with PAH had significantly higher levels — known as upregulation — of 813 lncRNAS and 527 mRNAs than those without the disorder. Meanwhile, the levels of 541 lncRNAs and 268 mRNAs were significantly lower, or downregulated in these patients, compared with those without PAH.

“These results revealed that PAH pathogenesis [development] was complex and the result of multiple gene interactions,” the researchers wrote.

Biological processes associated with the differentially expressed mRNAs (and their associated proteins) included immune responses, oxygen binding and transport, and cell-to-cell communication.

The researchers highlighted two differentially expressed genes: CXCL14, associated with inflammation and immune regulation, and PARP2, which is tied to DNA damage repair.

The top 50 mRNA with altered levels were grouped in a protein-protein network. Ten hub mRNAs were identified, associated with biological processes consistent with PAH, such as muscle function, regulation of inflammatory response, response to toxic substances, and blood clotting.

Then, the scientists identified two lncRNAs with the highest correlation with two of the hub mRNAs, namely lncRNA-TCONS_00008552 and lncRNA-ENST00000433673. In the blood samples of PAH children, only lncRNA-TCONS_00008552 was significantly increased compared with children without PAH.

According to the researchers, lncRNA-TCONS_00008552 might act as an activator or inhibitor of genes related to PAH.

“This study bolsters our understanding of the role of lncRNA in PAH occurrence and development and indicates that lncRNA-TCONS_00008552 is a novel potential molecular marker for PAH,” the researchers concluded.

The team noted that while they did not explore further the mechanism of action of this lncRNA, these molecules can be stably expressed in the blood, and have potential to be used as biomarkers.

A Conversation With Rare Disease Advocates