Micromolecules may keep the aorta intact

Therapy Breakthroughs 3. okt 2017 2 min Principal investigator Sebastian Albinsson Written by Morten Busch

When the wall of an aortic blood vessel is weakened, small balloon-like bulges called aneurysms are created. If these burst, they result in death in 8 of 10 cases. Researchers are seeking the mechanisms behind this weakening, which is regulated by microscopic molecules that determine the genetic expression. The effort now is to copy and increase the number of micromolecules to restore vascular strength.

When the enormous pressure from blood flowing through our arteries is suddenly directed at a weak point in the blood vessels, the risk of a rupture increases tremendously. Aneurysms in the aorta, the main artery in the human body, are therefore among the 10 most common causes of death related to cardiovascular diseases. Research in recent years has revealed why aneurysms occur and thus also discovered possible ways to prevent them.

“The bulges in aneurysms occur because the arterial wall is weakened. This is caused in part by changes in the structure of networks of actin proteins in smooth muscle cells. We hope that copying and increasing the number of some of these molecules that regulate actin filaments will enable people to restore vascular strength so that they can survive aneurysms,” explains Sebastian Albinsson, Principal Investigator, Molecular Vascular Physiology, Department of Experimental Medical Science, Faculty of Medicine, Lund University.

Affects muscle genes

The long chains of the actin protein normally ensure that the smooth muscles can contract in the colon, stomach and arteries. They also ensure that the arteries can withstand the pressure and the mechanical stresses to which they are subjected.

“If the formation of the actin chains changes, this affects both the structure and the flexibility of the arteries and thus significantly increases the risk of an aneurysm. We are therefore attempting to understand why the dynamics of the actin chains change and how to prevent this.”

The process in which the actins bind together in long protein chains affects the genes associated with arterial smooth muscle, in a positive feedback loop. This occurs when the myocardin-related transcription factor (MRTF) is released. However, in addition to directly influencing transcription of protein-coding genes, such as actin, MRTF also influences the production of several non-coding microRNAs that are highly expressed in smooth muscle cells.

“This means that several ultra-short RNA sequences are generated, but instead of being converted into proteins in the same way as messenger RNA molecules, these microRNAs function as regulators of protein translation by binding to messenger RNA and inhibiting protein synthesis.”

Death can occur in minutes

This new knowledge may turn out to be extremely important because there are already various examples of drugs being produced that can influence the number of microRNAs directly or indirectly by either binding to or resembling the relevant microRNA.

“If microRNAs can be bound, their effect on the regulation of cells can be eliminated, while producing analogues that increase the quantity of specific microRNAs could increase the effect commensurately. We can thus potentially regulate the activity of the genes that guide the production of the actin filaments or other important functions in the smooth muscle around the blood vessels.”

Among Danes older than 70 years, 2–4% have an aneurysm of the aorta, but the resulting bulges often produce no symptoms. But if they rupture, blood can flow into the abdominal cavity, and death occurs in minutes and few people reach the hospital.

“Today, if an aneurysm is discovered, we have to assess whether to operate. The risk associated with major surgery versus the risk of a rupture need to be considered. If we can instead learn how to regulate the mechanisms that cause aneurysms, we can probably provide treatment rather than operate and prevent many deaths.”

Molecular regulation of arterial aneurysms: role of actin dynamics and microRNAs in vascular smooth muscle” has been published in Frontiers in Physiology. In 2017, the Novo Nordisk Foundation awarded a grant to Sebastian Albinsson for the project In Vivo Targeting of Diabetes-associated MicroRNAs and Transcription Factors using Locked Nucleic Acid (LNA)-based Therapeutics in Diabetic Vascular Disease.

PhysiologyCardiac and Cardiovascular Systems Smooth muscle, Vascular physiology, microRNA, Vascular disease, hypertension

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