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Non-coding RNA in Vascular Ageing

Periodic Reporting for period 4 - NOVA (Non-coding RNA in Vascular Ageing)

Reporting period: 2019-10-01 to 2021-03-31

The main disease in the elderly is cardiovascular disease (heart disease). In the next decades the general population in the European Union will gradually become older and heart disease numbers will also increase. It is therefore important to understand what processes contribute to ageing-induced cardiovascular disease. In this project we studied which processes contribute to ageing in hearts and blood vessels. We focused mainly on the cells that line the inner side of blood vessels and form the interface between the blood and underlying tissue. It is known that these cells become weaker with increasing age. It is not completely understood which molecular processes in these cells contribute to this decline in function with ageing.
To identify novel therapeutic possibilities, we studied a special class of molecules: The so-called non-coding RNAs, which, in contrast to coding RNAs, do not contain instructions on how to form proteins, but rather function as active regulator themselves. We first wanted to know which of these non-coding RNAs are increased or decreased by ageing in endothelial cells. We identified several of these molecules that are either increased or decreased when comparing old and young endothelial cells. Importantly, we then found that altering the levels of these molecules changed the health of the endothelial cells. These molecules can therefore potentially be used as a therapeutic to improve endothelial cell and cardiovascular health in the elderly.
We set out to identify non-coding RNAs in endothelial cells that could perhaps be used therapeutically to treat cardiovascular disease in the elderly. We used data from isolated endothelial cells from young and old mice, and also human endothelial cells, isolated from umbilical veins, that we artificially aged in a Petri dish. Using so-called next generation RNA sequencing, we were able to find thousands of non-coding RNA molecules that were altered by aging. We then systematically studied the most promising non-coding RNA molecules one-by-one. The potential therapeutic use of several of these has been put in a patent. We also published scientific articles on each of these molecules in which we describe how these non-coding RNAs affect endothelial cell function in ageing.
The main findings are summarized here:
1. LncRNA Meg3 controls endothelial cell aging, published in Journal of the American College of Cardiology, 68(23), 2016, 2589-2591.
2. LncRNA H19 regulates endothelial cell aging, published in Cardiovasc Res. 2019 115(1):230-242.
3. LncRNA Lassie (linc00520) regulates endothelial barrier function, published in Commun Biol. 2020 3(1):265
4. Long Non-coding RNA Aerrie Controls DNA Damage Repair via YBX1 to Maintain Endothelial Cell Function, Front Cell Dev Biol. 2021 8:619079
We were the first to describe non-coding RNAs that regulate aging processes in endothelial cells. We also developed novel molecular biology methods to measure and characterize non-coding RNAs that are being used by other scientists as well now. Next to offering insights into the biology of cardiovascular ageing, our project also highlights therapeutic targets to treat aging-induced heart disease in the elderly.
Endothelial aging and H19 summary