Lipoproteins transport lipids within the bloodstream to all tissues where they are used as fuel or building blocks. The lipoproteins are spherical particles with a hydrophobic core containing cholesteryl esters and triglycerides, and a surface consisting of phospholipids. They also contain proteins, with apolipoproteins as the main functional and structural component. When lipoproteins enter the arterial wall, they can get trapped and modified, which then starts atherogenesis. We want to know why and how this happens.
Atherosclerotic cardiovascular diseases (ASCVD) are the primary cause of mortality worldwide. ASCVD is driven by the retention and modification of lipoprotein particles in the arterial wall. The main lipoproteins that enter the arterial wall and cause atherogenesis are cholesterol-rich low-density lipoproteins (LDL) and smaller, triglyceride-rich very-low-density lipoproteins (VLDL). LDL especially is very well studied as its’ plasma levels are a causal risk factor for ASCVD.
Plasma levels of atherogenic lipoproteins alone don’t fully cover the ASCVD risk of a person. We analyze LDL quality which is different from person to person and which is an independent risk factor for ASCVD. We have developed assays to measure the proatherogenic properties of LDL particles, for example the tendency of LDL to get trapped by extracellular matrix components in the arterial wall, or the speed of LDL aggregation. We also use proteomics and lipidomics techniques to analyze the composition of lipoproteins.
Lipoproteins, especially if they are modified either in circulation or after being trapped in the arterial wall, can cause inflammation. This inflammation is a main part of the progression of ASCDV. We study how these particles get taken up and affect various cell types in the arterial wall.
We currently focus on two main cell types, the endothelial cells lining blood vessels, and phagocytes that reside in the underlying tissue. Minimally modified lipoproteins from the circulation can be internalized by endothelial cells, which activates the cells and initiates endothelial dysfunction. Endothelial dysfunction contributes to the plaque development due to increased influx of lipoproteins and immune cells to the underlying tissue.
Intimal phagocytes have two main functions: firstly, they ingest and digest the modified lipoproteins and remove the particles from the tissue. Secondly, they remove distressed and dying cells from the inflamed area and reduce the buildup of a necrotic core in a process called efferocytosis. However, both processes are impaired during atherogenesis.
We use lipoproteins isolated from human atherosclerotic plaques and multi-OMICs approaches and biochemical assays to study the cellular responses in vitro. Ultimately, we aim to stabilize inflammatory processes and attenuate the development of vulnerable atherosclerotic plaques.