Blocking microRNAs to fight atherosclerosis
Researchers at Emory University and the Georgia Institute of Technology, working under the guidance of Professor Hanjoong Jo, have developed a method to combat atherosclerosis based on the use of microRNAs.
With atherosclerosis, a gradual thickening of the arterial wall occurs due to the deposition of lipids and cholesterol on it. This process can lead to the formation of atherosclerotic plaques and, eventually, to heart attacks and strokes.
As a rule, foci of atherosclerosis are localized in branching or curved regions of the arteries, which is due to the peculiarities of blood flow. Experts believe that a constant stable blood flow contributes to maintaining the health of the arteries, while uneven or turbulent blood flow can contribute to the development of atherosclerosis.
The authors developed an animal model that allows triggering the rapid formation of atherosclerotic changes in specific areas by partially limiting the blood flow in the carotid artery of mice. To speed up the process, the apolipoprotein E (ApoE) gene, which plays an important role in the elimination of cholesterol and lipids from the blood, was disabled in animals kept on a fat-rich diet. This model allows researchers to compare molecules activated in the cells of the endothelium – the membrane lining the inner surface of blood vessels – healthy (on the one hand) and atherosclerotic (on the other hand) arteries of animals.
As part of the work, the researchers paid attention to microRNAs – short RNA sequences capable of simultaneously suppressing the activity of many genes. Recently, the ability of microRNAs to move from one cell to another has been established, thus regulating the course of various processes, including those underlying the development of atherosclerosis. Among the analyzed microRNAs, the greatest attention of the authors was attracted by the miR-712 molecule, the activity of which changed most strongly with impaired blood flow in the atherosclerosis model.
Violation of blood flow stimulated the synthesis of miR-712 by endothelial cells, which, in turn, inhibited the activity of the TIMP3 gene, which suppresses endothelial inflammatory processes under normal conditions.
To the surprise of scientists, it turned out that miR-712 is one of the fragments remaining from the long RNA involved in the formation of ribosomes – organelles contained in large quantities in the cell and playing an extremely important role in the synthesis of protein molecules.
Using the technology of "blocked nucleic acids", the authors analyzed the effects of suppression of miR-712 activity in the body. In a mouse model of rapid development of atherosclerosis, anti-miR-712 drug had a pronounced positive effect on the condition of blood vessels. Without the drug, atherosclerotic plaques blocked the lumen of the arteries by 80%, while the drug halved the severity of the blockade. Similar results were obtained in another animal model characterized by slower development of atherosclerosis.
The authors claim that human miR-205 microRNA is an analog of mouse miR-712 and has a similar effect on inflammatory processes in the endothelium. Currently, they are developing methods for delivering anti-miR-205 drugs to the heart or endothelial cells using nanotechnology, which would provide a pronounced therapeutic effect without undesirable side effects.
Article by Dong Ju Son et al. The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis is published in the journal Nature Communications.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru according to the materials of MedicalNewsToday:
Targeting micro RNA to halt atherosclerosis.
27.12.2013