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

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by Steve Bryson, PhD |

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Seven long noncoding RNA molecules were found to be associated with the development of pulmonary hypertension (PH) in an early study in rats, scientists reported.

The researchers noted that some of these RNAs are known to regulate immune and inflammatory response pathways, which may participate in PH.

“Our study contributes to a better understanding of the [development of PH] and the role of [noncoding RNAs] in disease progression,” they wrote. “Further research is needed to determine the molecular mechanisms by which [noncoding RNAs] play a role in [PH] generation and development.”

The study, “Construction and analysis of the abnormal lncRNA–miRNA–mRNA network in hypoxic pulmonary hypertension,” was published in the journal Bioscience Reports.

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Blood vessels that pass through the lungs narrow in PH, leading to abnormally high blood pressure, making it harder for the heart to pump blood. As a result, the heart becomes enlarged and gradually weakens. Although many studies have investigated PH, many of the underlying biological mechanisms that contribute to the disease have not been fully explored.

Messenger RNA (mRNA) is the molecule that carries instructions to make proteins from corresponding genes in DNA. MicroRNAs (miRNA) are small segments of RNA that bind to and silence mRNA, modulating protein production.

Long noncoding RNAs (lncRNAs) are longer segments of RNA initially thought to be non-functional. However, growing evidence suggests lncRNAs are widely involved in disease processes by interacting with and blocking miRNA. In this way, long noncoding RNAs may also work to regulate protein production.

Many lncRNAs are generated at different levels (differentially expressed) in rat models of PH compared to healthy rats. These findings led to the discovery of PH-related lncRNAs, but how lncRNAs, miRNAs, and mRNAs interact in PH has not been examined.

Researchers in China constructed a lncRNA–miRNA–mRNA network by screening for differentially expressed RNAs in rats with induced PH to further understand the disease’s underlying biology.

Healthy rats were exposed to low oxygen conditions (hypoxia), which led to thickened pulmonary blood vessels, high blood pressure in the heart, and enlarged heart tissue, mimicking PH in people.

Compared to healthy rats, PH rats had significantly higher expression of 31 lncRNAs (up-regulated) and lower expression of 29 lncRNAs (down-regulated). A total of 15 miRNAs were up-regulated and five were down-regulated, while 534 mRNA molecules were up-regulated and 161 were down-regulated.

Biological processes related to the differentially expressed mRNAs (and their associated proteins) included immune and inflammatory responses, the migration of immune cells, cellular response to the immune signaling protein (cytokine) interleukin-1 (IL-1), and the cell cycle.

Biological pathway analysis found these messenger RNAs were involved in cell cycle pathways, the IL-17 signaling pathway, the interactions between cytokines and their corresponding receptors, and the Toll-like receptor signaling pathway, critical for immune system function.

Computer analysis then predicted which up-regulated lncRNAs target specific down-regulated microRNAs, and which down-regulated microRNAs target up-regulated messenger RNAs. An lncRNA–miRNA–mRNA network was constructed by combining lncRNA–miRNA pairs and miRNA–mRNA pairs.

The final PH-related network was composed of seven lncRNAs that interacted with 16 microRNAs, which in turn regulated 144 messenger RNAs.

The 144 network mRNAs were associated with the cell cycle, transport of inorganic molecules (those without carbon-hydrogen bonds), small molecule binding, cytokine–cytokine receptor interactions, and the p53 signaling pathway, which responds to stressors that can disrupt DNA replication and cell division. In addition, they identified 19 genes central to the network.

The expression of nine selected RNAs (three lncRNAs, two miRNAs, and four mRNAs) was consistent with the results, as confirmed by a method called qualtitative polymerase chain reaction.

“Thus, we propose that the seven [differentially expressed] lncRNAs in the [RNA] network may serve as molecular sponges of the corresponding miRNAs to regulate mRNA expression and participate in the occurrence and development of [PH],” the scientists wrote.

Stressing that further studies are needed to better determine the processes linking noncoding RNAs with PH development, the team highlighted the small number of animals used was one of their study’s limitations.