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Review
. 2022 Mar 3:9:841545.
doi: 10.3389/fcvm.2022.841545. eCollection 2022.

Modified Lipoproteins Induce Arterial Wall Inflammation During Atherogenesis

Martina B Lorey  1   2 , Katariina Öörni  1   2 , Petri T Kovanen  1
Affiliations
Review

Modified Lipoproteins Induce Arterial Wall Inflammation During Atherogenesis

Martina B Lorey et al. Front Cardiovasc Med. .

Abstract

Circulating apolipoprotein B-containing lipoproteins, notably the low-density lipoproteins, enter the inner layer of the arterial wall, the intima, where a fraction of them is retained and modified by proteases, lipases, and oxidizing agents and enzymes. The modified lipoproteins and various modification products, such as fatty acids, ceramides, lysophospholipids, and oxidized lipids induce inflammatory reactions in the macrophages and the covering endothelial cells, initiating an increased leukocyte diapedesis. Lipolysis of the lipoproteins also induces the formation of cholesterol crystals with strong proinflammatory properties. Modified and aggregated lipoproteins, cholesterol crystals, and lipoproteins isolated from human atherosclerotic lesions, all can activate macrophages and thereby induce the secretion of proinflammatory cytokines, chemokines, and enzymes. The extent of lipoprotein retention, modification, and aggregation have been shown to depend largely on differences in the composition of the circulating lipoprotein particles. These properties can be modified by pharmacological means, and thereby provide opportunities for clinical interventions regarding the prevention and treatment of atherosclerotic vascular diseases.

Keywords: atherogenesis; endothelial dysfunction; foam cell; inflammation; modified lipoproteins.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Sites of modification in apoB-100-containing lipoproteins. Surface modifications include modifications of apo-B100 by proteases, oxidation by superoxide anion radicals (O2-), glycosylation by advanced glycosylation end-products (AGEs), binding of malondialdehyde (MDA) adducts, or acetylation (Ac). Phospholipids can be oxidized as well as hydrolyzed by phospholipase A2 (PLA2) to lysophosphocholine (LPC) and a fatty acid (FA), while sphingomyelins can be hydrolyzed by sphingomyelinase (SMase) to yield ceramides and phosphorylcholines. Core modifications include cholesteryl ester oxidation and well as hydrolysis by cholesterol esterase (CEase) or lysosomal acid lipase (LAL) to yield unesterified cholesterol and a fatty acid (FA). Triacylglycerol can be hydrolyzed by LAL to diacylglycerol and a fatty acid (FA).
Figure 2
Figure 2
Effects of lipoproteins on macrophages and endothelial cells. Upon phagocytosis, modified lipoproteins are hydrolyzed in the lysosomes of macrophages. Cholesterol is then transported to the ER where it is packaged in lipid droplets for storage. It can also crystalize in the lysosomes, leading to lysosomal dysfunction and the release of reactive oxygen species (ROS) and cathepsins, which in turn activate cytosolic inflammasomes. NF-κB signaling is induced and the activated macrophages secrete leukocyte chemotactic molecules, pro- as well as anti-inflammatory cytokines, and proteases. In endothelial cells, lipoproteins can be transported through the cell via transcytosis, mediated by binding to scavenger receptor B1 (SR-B1) and activin-like kinase 1 (ALK1). If the lipoproteins have been modified, they can also bind to lectin-type oxidized LDL receptor 1 (LOX-1) and then targeted to the lysosomes after internalization. LOX-1 activation leads to decrease in nitric oxide (NO) and increase in reactive oxygen species (ROS), the latter being able to trigger NLRP3 inflammasome activation. Activated endothelial cells increase the expression of adhesion molecules which accelerates leukocyte extravasation, and they also secrete leukocyte chemotactic factors, as well as pro-inflammatory cytokines.
Figure 3
Figure 3
Lipoproteins modified in the intima induce inflammation. Lipoproteins smaller than 80 nm can enter the intima by transcytosis, they get trapped by proteoglycans and during retention they are exposed to enzymes secreted by intimal cells. Modified lipoproteins tend to aggregate, depending on the modification cholesterol crystals can form. Modified lipoproteins also are recognized by antibodies and form immunocomplexes in the intima. The aggregates and crystals can be phagocytized by macrophages or dendritic cells, which can form foam cells or activate T cells, respectively. Mast cells are degranulated during atherogenesis, leading to matrix degradation and lipoprotein degradation. Activated macrophage foam cells secrete more enzymes thus increasing the rate of modification, they secrete cytokines inducing an inflammatory state in the intima, as well as chemoattractants. Endothelial cells either directly by contact with modified lipoproteins or due to pro-inflammatory cytokines from foam cells themselves secrete chemoattractants and increase expression of adhesion molecules, increasing the rate of leukocyte extravasation into the intima. Endothelial activation and dysfunction also lead to a higher rate of lipoproteins entering the intima.
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