A study recently published in the Journal of Clinical Laboratory Analysis shows that levels of the long noncoding RNA LINC00963 correlate with histological and molecular changes seen in pulmonary arterial hypertension (PAH).

The experimental study conducted by Yang et al used ex vivo human pulmonary arterial smooth muscle cells (PASMC) and a PAH mouse model; the PAH mice were divided into a group that was exposed to hypoxic conditions and a control group. In mice, hypoxia generated thicker arterial walls in the lungs and overall higher right ventricular systolic pressure, mean pulmonary artery pressure, and right ventricular hypertrophy index.

Quantitative real-time polymerase chain reaction for LINC00963 and profilin 1 (PFN1) revealed that the hypoxia-induced cells had a higher expression of those markers while showcasing decreased microRNA (miRNA)-328-3p compared to the control group.


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Moreover, after transfecting hypoxic cell cultures with silencing RNA-LINC00963 complex (si-LINC00963), the levels of vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF-2), and hypoxia-inducible factor α (HIF-α) decreased, and the viability and migration of PASMCs also diminished. Likewise, the transfection of miRNA-328-3p mimics was conducted with the same results. A miRNA-328-3p inhibitor and increased PFN1 independently attenuated the positive effects of si-LINC00963.

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The authors noted, “The results implied that high expression of PFN1 is closely associated with the exacerbation of PAH. Meanwhile, PFN1 is found to be the downstream target of miR-328-3p. Therefore, we further made a hypothesis that the LINC00963/miR-328-3p axis may interact with PFN1 to affect PAH.”

They added, “Our rescue experiments demonstrated that overexpression of PFN1 reversed the inhibiting effects of LINC00963 knockdown on viability, migration, and the levels of VEGF, FGF-2, and HIF-α. Taken together, we considered that silencing of LINC00963 can attenuate PAH through sponging miR-328-3p and mediating PFN1.” 

Previous researchers have noted the upregulating effect of LINC00963 on metastasis and proliferation of nonsmall cell lung cancer, and although they are different entities, this malignancy shares some pathophysiological aspects with PAH, hence the hypothesis that LINC00963 could play a role in this disease.

“We suggested that [LINC00963] may act as a sponge of miR-328-3p in PAH progression. As expected, we found the suppressive effects of LINC00963 silencing on viability, migration, and the levels of VEGF, FGF-2, and HIF-α were rescued by miR-328-3p inhibition. The results suggested that silencing of LINC00963 affects PAH by modulating miR-328-3p,” the authors explained, suggesting a possible novel therapeutic target for PAH. 

Reference

Yang C, Rong R, Li Y, Cheng M, Luo Y. Decrease in LINC00963 attenuates the progression of pulmonary arterial hypertension via microRNA‐328‐3p/profilin 1 axis. J Clin Lab Anal. Published online March 29, 2022. doi:10.1002/jcla.24383