Potential Way of Treating PAH Seen in Blocking Specific MicroRNA
Blocking the activity of a small RNA molecule called microRNA-30a eased alterations in heart structure and blood vessel architecture in mouse models of pulmonary arterial hypertension (PAH), a new study reports.
Results also showed that this molecule is present at abnormally high levels in PAH patients, supporting its potential as a therapeutic target.
The study, “Inhibition of MicroRNA-30a Alleviates Vascular Remodeling in Pulmonary Arterial Hypertension,” was published in the journal Molecular Therapy Nucleic Acids.
MicroRNAs are short RNA molecules with about 22 nucleotides, the building blocks of RNA and DNA. Unlike the better-known messenger RNA (mRNA), microRNA do not code for proteins — instead, these molecules regulate the activity of other genes.
Prior research has suggested that a specific microRNA, called microRNA-30a (MiR-30a), is present at abnormally high levels in people who have had heart attack, as well as in cultured cardiac cells in response to low oxygen. However, the role of this microRNA in PAH has not been thoroughly studied.
A team of scientists in China measured miR-30a levels in blood samples from 81 PAH patients, as well as 49 people without PAH (controls). Both groups were about evenly divided by sex, and the average age was 54.3 years in the PAH group and 46.6 among controls.
Results showed that miR-30a levels were significantly higher, on average, among the PAH patients.
The team also showed that miR-30a levels were increased in pulmonary artery smooth muscle cells — muscular cells of the pulmonary artery wall — under oxygen-deprived conditions. They further demonstrated that miR-30a could regulate the level of a protein called P53, which helps to control cell death and survival, in pulmonary artery smooth muscle cells. P53 is a known target of miR-30a in other cell types, but whether it is a target in these smooth muscle cells was not clear.
The researchers then tested the role of miR-30a in two different mouse models of PAH — one induced with a chemical called monocrotaline, and the other in response to low oxygen.
In both models, mice that were genetically engineered to lack miR-30a showed improvements in circulatory health. For example, blood pressure in the right ventricle — the part of the heart that pumps blood to the lungs, which is stressed in PAH — of these mice was reduced. Lesser right ventricle hypertrophy, or abnormal growth of heart muscle, also was seen, as was lesser scarring of cardiac muscle and the right ventricle.
Further analyses suggested that miR-30a acts to block apoptosis — “programmed” cell death, as apposed to death caused by injury — in small blood vessel cells of the lungs. Deletion of miR-30a enhanced apoptosis, which helped to ease the changes that narrow blood vessels in PAH.
In one of the mouse models, the team demonstrated that blocking miR-30a activity using a specially designed molecule treatment called an antagomir could enhance apoptosis and alleviate signs of PAH.
“This study is the first to identify the role of miR-30a in PAH and describe its therapeutic effect by inhibition of miR-30a,” the researchers concluded.
Blocking miR-30a, they added, is “a novel and promising approach for the treatment of PAH.”