MicroRNAs may hold key
to treating pulmonary arterial hypertension
By Amanda Chase, PhD
February 23, 2021
The heart is composed of four chambers: (1) the right atrium receives blood from the body and pumps to the right ventricle, (2) the right ventricle pumps blood to the lungs where it is loaded with oxygen, (3) the left atrium receives oxygenated blood from the lungs and pumps to the left ventricle, and (4) the left ventricle pumps blood to the rest of the body. This is a highly coordinated process, and disruptions can lead to cardiovascular diseases, the most common cause of death globally. Pulmonary arterial hypertension (PAH) is a condition caused by an obstruction of the small arteries of the lungs that leads to decreased blood flow and increased blood pressure. The right ventricle (RV) must work harder to pump blood to the lungs, which leads to structural and functional remodeling, and ultimately results in a weakened heart muscle and can result in heart failure. PAH is considered a progressive disease in that it gets worse over time, and there are about 500-1000 new cases a year in the US. Currently, there are treatments to reduce symptoms, but no cure. Understanding the molecular mechanisms, currently unknown, has the potential to provide avenues for treatment of PAH.
Ronglih Liao, PhD, Professor of Medicine at Stanford School of Medicine, and Stanford Cardiovascular Institute member, sought to understand the molecular mechanisms that contribute to RV dysfunction in a recent publication in the Journal of Molecular and Cellular Cardiology. Dr. Liao and her team showed that microRNA-21 (miR-21) is an important regulator of cardiomyocyte (heart cell) biology, especially in RV structural and functional remodeling.
MicroRNAs (miRNAs/miRs) are small, single-stranded RNAs, usually about 22 nucleotides in size. They are non-coding, meaning they do not become proteins, but they are involved in RNA silencing and can regulate gene expression. MiR-21, specifically, has been shown to be increased in failing hearts, and is known to play a key role in cardiomyocyte proliferation, cell death, and hypertrophy (organ enlargement due to increased cell size). Dr. Liao and her team were able to show for the first time that miR-21 expression is increased and plays a critical role in functional and structural changes in a large animal model the more closely resembles the human heart that then usual rodent model.
Importantly, they also showed that increased expression of miR-21 increased expression of proteins needed for mitosis (cell division) but not cytokinesis (cytoplasmic division of the cell at the end of mitosis), perhaps contributing to the observed structural remodeling and declined function of the RV. Consequently, these results show the potential for miR-21 as a therapeutic target for treatment of RV dysfunction as a result of PAH.
Other authors affiliated with the Cardiovascular Institute include Seema Dangwal, Chih-Hsin Hsu, and Keven Alexander.