Small RNA Molecule May Slow Pulmonary Vascular Remodeling to Treat PAH, Study Suggests
A tiny RNA molecule known as microRNA-410 (miR-410) was seen to slow the proliferation of endothelial cells in the lung and ease pulmonary vascular remodeling in a mouse model of pulmonary arterial hypertension (PAH).
These findings suggest that raising miR-410 levels in the lung may offer a way of treating people with this disease, researchers report.
The study, “MicroRNA410 Inhibits Pulmonary Vascular Remodeling via Regulation of Nicotinamide Phosphoribosyltransferase,” was published in the journal Nature Scientific Reports.
Nicotinamide phosphoribosyltransferase (NAMPT) is a protein with proinflammatory activity outside cells and enzymatic activity inside cells. Higher than usual levels of NAMPT in pulmonary artery endothelial cells (PAECs) — which line the interior of blood vessels — are associated with PAH progression and vascular remodeling in the lung. Although it remains unclear exactly how elevated NAMPT levels aggravate PAH, suppressing this enzyme may be a treatment approach.
miRs are increasingly linked to cardiac and vascular diseases, including PAH, in scientific studies.
Researchers at University of Illinois at Chicago, University of Maryland School of Medicine, and Indiana University explored if miRs might help to regulate NAMPT levels, and so modulate the proliferation, migration, and death of PAECs.
The team used computer-based methods to find miRs targeting a specific region of the genetic coding sequence of NAMPT. They found five different miRs, of which miR-410 had the highest probability of being target specific. Prior research has associated this small RNA molecule with cell proliferation and survival.
Laboratory experiments with human PAECs that involved overproducing and suppressing miR-410 confirmed that this particular miR could effectively target NAMPT. Increased levels of miR-410 boosted NAMPT production, while miR-410 inhibition had the opposite effect.
Upon further analysis, the team also found that the presence of vascular endothelial growth factor (VEGF) — known to induce endothelial cell proliferation and drive PAH disease processes — was linked to lower miR-410 levels, and higher RNA and protein levels of NAMPT.
Subsequent analyzes using small molecules that either mimic or suppress miR-410 in PAECs confirmed the previous findings, with NAMPT showing an miR-410 dependent response.
High levels of the miR-410 mimics prevented basal and VEGF-induced proliferation and migration of human PAECs (hPAECs), while elevated levels of miR-410 inhibitors served to boost both processes. The data also revealed that overproduction of miR-410 led to the death of human PAECs in a dose-dependent manner, in contrast with NAMPT that is known to support hPAEC survival.
Exposing mice to low oxygen significantly dropped miR-410 levels in the lung by day seven, but they returned to previous (baseline) levels by days 14 and 28. During these same 28 days of low oxygen, NAMPT behaved in an opposite manner, with an increase followed by a reduction.
Administration of miR-410 mimics to these animals led to significant lessening of the right ventricular systolic pressure, prevented right ventricular hypertrophy (enlargement) and pulmonary vascular remodeling compared to placebo-treated mice. miR-410 mimics also lowered NAMPT levels in the lung while the mice were under low oxygen.
Neither of these effects were seen in mice on normal oxygen levels. But protein levels of NAMPT were lower than usual in lung endothelial cells in both hypoxia and normal oxygen conditions.
“Our results describe a novel role for miR-410 in controlling the proliferation, apoptosis, and migration of hPAECs, and affecting pulmonary vascular remodeling via regulation of NAMPT expression,” the researchers wrote. “Overexpression of miR-410 in the pulmonary circulation may have a therapeutic effect in PAH.”
However, the team cautioned that studies in samples from patients with PAH and animal models of severe disease are needed to validate these results.