Targeting miRNA-214 May Decrease Cell Proliferation in PAH, Study Reports

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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PAH study

A microRNA, called miR-214, promotes excessive cellular proliferation in pulmonary arterial hypertension (PAH), and decreasing its expression may significantly impair phenotype changes in the lung vasculature in PAH, researcher report.The study, “MEF2C-MYOCD and Leiomodin1 Suppression by miRNA-214 Promotes Smooth Muscle Cell Phenotype Switching in Pulmonary Arterial Hypertension,” was published in the open access journal PLOS One.

PAH is characterized by excessive cellular proliferation, and smooth muscle cell switching from a contractile to a synthetic state, which helps propagating vessel wall remodeling and occlusion.

Maintaining smooth muscle cells contractile phenotype is controlled by the interplay between myocyte enhancer factor 2C (MEF2C) and another factor, the myocardin (MYOCD). However, the molecular mechanisms underlying the MEF2C- MYOCD interplay are largely unknown.

A team of researchers hypothesized that a class of short non-coding RNAs, called microRNAs (miRs), could modulate MEF2C-MYOCD signaling and, consequently, a pro-proliferative, synthetic smooth muscle cell phenotype. The researchers focused specifically on miR-214, which is ubiquitously expressed in vasculature, and how it may control several factors of the signaling cascade, namely MEF2C, MYOCD, and LMOD1 expression.

Researchers determined miR-214 expression in smooth muscle cells isolated from a PAH patient cohort, and commercially obtained human pulmonary artery smooth muscle cells (hPASMCs) exposed to hypoxia.

They found that miR-214 was upregulated in PAH samples, when compared to control hPASMCs and also to commercially obtained hPASMCs exposed to hypoxia. The increase in miR-214 expression was accompanied by MEF2C, MYOCD, and SMC contractile protein down-regulation. Moreover, researchers discovered that overexpression of miR-214 down-regulated the expression of MEF2C, LMOD1, and other MYOCD-regulated contractile proteins, including MYH11, smoothelin, and CNN1. By inhibiting miR-214, researchers restored the expression of smooth muscle cell contractile proteins. In fact, further studies showed that both LMOD1 and MEF2C are direct and functional targets of miR-214.

Results showed that miR-214 is a direct regulator of contractile proteins, specifically by modulating the MEF2C-MYOCD-LMOD1 signaling pathway. Targeting miR-214, therefore, is a potential strategy to block smooth muscle cells changes and impair excessive cellular proliferation in vasculature disorders, including PAH.

PAH is a serious condition characterized by high blood pressure in the lung arteries, with vessels becoming narrowed, blocked or destroyed. The build up in pressure ultimately leads to heart right ventricular failure and death.

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