For most drug therapies, researchers test on animal models of a disease before testing on humans. Recently, using microRNA-483, a small RNA molecule, on rat models of PAH reduced symptoms associated with the condition. This suggests that microRNA could be used to effectively treat PAH by regulating gene activity. Check out the full study results in EMBO Molecular Medicine.
Pulmonary Arterial Hypertension (PAH)
Pulmonary arterial hypertension (PAH) is a chronic, progressive, and sometimes inherited form of high blood pressure. It causes the pulmonary arteries to thicken over time, making it more difficult for the heart to pump blood and receive oxygen. When less oxygenated blood goes to the brain and body, our health suffers. Further, the heart muscle becomes weak and damaged. It tends to affect females more than males, particularly between the ages of 30 and 60.
In some cases, PAH results from a BMPR2 gene mutation. However, other causes include HIV, drug use, sickle cell disease, lung or liver disease, heart disease or congestive heart failure, and autoimmune conditions. Symptoms include:
- Dizziness or fainting spells
- Shortness of breath which worsens during activities
- Chest pain and pressure
- Swelling in the abdomen and lower extremities
- Heart palpitations
- Cyanosis (a blue appearance to skin and lips)
Learn more about PAH here.
Throughout your body, you have a number of endothelial cells, or cells that line blood vessels and form a barrier between the vessels and body tissue. These cells play a number of roles, such as blood clotting, blood pressure, water regulation, and inflammation. But when these cells don’t function properly, like in PAH, levels of cytokines (pro-inflammatory molecules) rise. Eventually, this leads to increased blood pressure. However, prior drug therapies were not very effective in targeting these damaged or non-functioning cells.
But researchers discovered that microRNAs, which can regulate gene activity, might be effective therapeutic targets. Utilizing these would help create customized and targeted therapies for patients with PAH.
Previously, one study noted that MicroRNA-483 (MiR-483) prevented fibrosis and improved endothelial cell function. So researchers wanted to understand whether miR-483 could benefit patients with PAH.
Studying the Effects of MiR-483 on PAH
First, researchers analyzed blood from healthy rats compared to rats with PAH to determine differing levels of miR-483. They found that animals with PAH had lower miR-483 levels, correlating with more severe conditions. Lower miR-483 levels were also associated with a higher mortality risk.
Next, researchers determined whether lower mRNA levels linked to endothelial cells. They began by isolating extracellular vesicles (EVs) from the blood of healthy rats and those with PAH. EVs play a role in cellular communication and protein transportation. Ultimately, researchers found that EVs from rats with PAH had less miR-483.
Then, researchers increased miR-483 levels in lab-grown human pulmonary arterial endothelial cells. As a result, they observed lower cell adhesion, cell death, metabolism, inflammation, migration, and proliferation processes.
Finally, researchers directly delivered miR-483 to the trachea of rat models. This:
- Reduced thickened blood vessels
- Suppressed genes related to PAH
- Reduced symptoms
- Improved survival rate and decreased mortality risk
- Reduced heart enlargement