O. Vieira Lab | What is the connection between atherosclerosis and lysosomal dysfunction?

GrupoOtilia20210922-01255From left to right: André Marques, Otília Vieira e Liliana Alves

What is the connection between accumulation of lipids in arteries and lysossomal dysfunction? The answer was published in Journal of Cell Science, in the research by Otília Vieira's group at CEDOC-NMS, Lysosomes in Chronic Human Pathologies & Infection, including Liliana Alves and André Marques.

They were able to identify a particular oxidized lipid, ChA, that leads to the accumulation of atherosclerotic plaques and the decreased functionality in lysosomes. They were also able to identify a potential therapeutic molecule that can revert this phenotype.

What discoveries led you to the research described in your publication?

Atherosclerosis is caused by an accumulation of lipid plaques in the inner lining of arteries, leading to their thickening or hardening. One of the main factors contributing to the development of atherosclerotic plaques is the uptake of oxidized low-density lipoproteins (oxLDL) by the cells of the artery wall, particularly macrophages and vascular smooth muscle cells (VSMCs). OxLDL accumulates in these cells and causes dysfunction of the lysosomal compartment, the recycling centre of the cell, leading to the transformation of these cells in pathological foam cells. Despite a lot of previous research into this topic, it remains unclear which components of these oxLDL trigger the loss of cellular homeostasis. To bridge this gap in knowledge, our group has identified and quantified cholesteryl hemiesters formed during LDL oxidation in plasma of cardiovascular disease (CVD) patients. We discovered that in CVD patients the most prevalent of these oxidized lipids is cholesteryl hemiazelate (ChA).

What were you trying to understand and what is the main discovery of this work?

In atherosclerotic lesions, vascular smooth muscle cells (VSMCs) represent half of the foam cell population, characterized by an aberrant accumulation of undigested fatty deposits within lysosomes, the recycling centres of cells. Loss of lysosome function impacts VSMCs homeostasis and disease progression. Understanding the molecular mechanisms underlying lysosome dysfunction in these cells is, therefore, crucial. Therefore, we decided to assess whether the most prevalent cholesteryl hemiester found in CVD patients - ChA - can induce lysosomal dysfunction and loss of cell homeostasis in a mice model of VSMCs.
Our data indicate that ChA is indeed able to induce lysosome dysfunction in VSMCs, leading to an exuberant accumulation of neutral lipids. We also found that VSMCs with these features proliferate and migrate less and become stiffer than control cells. Altogether, these data suggest that ChA is pathogenic towards VSMCs with potential impact in atherosclerosis progression and in their protective role in plaque stability.

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Red arrows showing enlarged lysossomes due to ChA treatment

Why is this important?

Cardiovascular diseases are the leading cause of mortality worldwide and atherosclerosis is the culprit for most of these pathologies. Understanding the molecular mechanisms that drive atherosclerosis is therefore fundamental to develop prevention strategies and effective therapies. Even though lysosome dysfunction is at the centre of plaque formation, very little is known about this process in VSMCs. In this work, we found that ChA accumulates in VSMCs and causes lysosome malfunction, recapitulating many of the effects seen with oxidized low-density lipoproteins (oxLDL), including induction of foam cell formation. We also demonstrate that, as consequence of these alterations, these cells become stiffer, migrating and proliferating less, which will contribute to the destabilization of atherosclerotic plaques.

Can you use an analogy to help us understand your work?

VSMCs act as “vacuum cleaners” within the artery wall by clearing accumulated lipoproteins and dead cells, thereby preventing the progression of atherosclerosis. With time, the appearance of oxidized lipids hampers the “vacuuming” abilities of these cells, in this way contributing to the formation of atheroma plaques filled with dead/necrotic cells and unprocessed lipids.

What questions remain to be asked?

We still need to understand whether ChA is the main “lipid offender” driving lysosomal dysfunction in artery cells. For that, in the future, we aim to compare the effects of this lipid with that of others we found in the plasma of CVD patients. We would also like to know whether the presence of this lipid in the circulation can be used as a marker to assist in the timely diagnosis of CVDs. Also, as we were able to identify an enzyme, lysosomal acid lipase (LAL) that is able to revert the foam cell phenotype caused by ChA, we need to investigate if it could become a therapeutic target for lysosomal dysfunction.

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Proposed Model for the Formation of Atherosclerotic Plaques

You can find the full article at Journal of Cell Science with the title "Cholesteryl hemiazelate causes lysosome dysfunction impacting vascular smooth muscle cells homeostasis" here.

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