Mechanistic Insights into the Oxidized Low-Density Lipoprotein-Induced Atherosclerosis

Abstract

Dyslipidaemia has a prominent role in the onset of notorious atherosclerosis, a disease of medium to large arteries. Atherosclerosis is the prime root of cardiovascular events contributing to the most considerable number of morbidity and mortality worldwide. Factors like cellular senescence, genetics, clonal haematopoiesis, sedentary lifestyle-induced obesity, or diabetes mellitus upsurge the tendency of atherosclerosis and are foremost pioneers to definitive transience. Accumulation of oxidized low-density lipoproteins (Ox-LDLs) in the tunica intima triggers the onset of this disease. In the later period of progression, the build-up plaques rupture ensuing thrombosis (completely blocking the blood flow), causing myocardial infarction, stroke, and heart attack, all of which are common atherosclerotic cardiovascular events today. The underlying mechanism is very well elucidated in literature but the therapeutic measures remains to be unleashed. Researchers tussle to demonstrate a clear understanding of treating mechanisms. A century of research suggests that lowering LDL, statin-mediated treatment, HDL, and lipid-profile management should be of prime interest to retard atherosclerosis-induced deaths. We shall brief the Ox-LDL-induced atherogenic mechanism and the treating measures in line to impede the development and progression of atherosclerosis.

Figure 1

Schematic network of atherosclerosis process. The LDL in the blood stream passes through the damaged endothelium (caused by hypertension, high cholesterol, smoking, and hyperglycemia) gaining entry into tunica intima. Damaged endothelial cells being compromised express adhesion molecules that capture the monocytes. Monocytes enter into the intima producing free radicals which oxidizes the LDL. Oxidized LDL attracts more white blood cells (monocytes) and more immune cells to the site, macrophages engulf Ox-LDL particles becoming over laden and turning into foam cells. Foam cells die releasing its content outside that again is engulfed by other macrophages eventually building a large lesion area. Progression into this, lesion turns into plaque gradually accumulating calcium slats, smooth muscle cells (from tunica media), collagen, and the foam cells. The plaque is stable under the endothelium until the endothelium just above gets compromised. The damaged endothelium could no longer produce inhibitors for blood clotting making it more vulnerable to enter into the vessel lumen. The clot attached to the vessel wall would make a thrombus that may break causing stroke or myocardial infarction.

Figure 2

LDL and Ox-LDL Structure. The hydrophobic core of LDL is made of around 170 triglycerides, 1500 cholesterol esters, a hydrophilic coat composed of 700 molecules of phospholipids, about 500 molecules of unesterified cholesterol, and a single large copy of the apolipoprotein B (ApoB) of 500 kDa. Gaining entrance into the endothelium, LDL gets oxidatively modified by ROS.

Figure 3

Artery is made of three layers: tunica intima, media, and adventitia.

Figure 4

Atherosclerotic artery. Atherosclerotic artery has a plaque build-up in the subendothelium making the lumen too small for a smooth blood flow.

Figure 5

Early and late atherosclerotic lesions. The figure is reproduced from Glass and Witztum [56] (under the Creative Commons Attribution License/public domain) “(Reprinted (Atherosclerosis: The Road Ahead) with permission from Elsevier (License number 4825741069515)).”(a) Cross section of a fatty streak lesion from the aorta of a cholesterol-fed rabbit immune stained for a macrophage-specific marker (micrograph courtesy of Wulf Palinski). (b) Cross section through a human coronary artery at the level of a thrombotic atherosclerotic lesion causing fatal myocardial infarction.

Figure 6

Schematic illustration of the role of Ox-LDL in atherosclerosis progression. Ox-LDL elicits atherosclerotic events right from their production in the subendothelium. Due to downregulated LDL receptors, the native LDL cannot be internalized by macrophages. Ox-LDL, via LOX 1 and other factors, activates endothelium for a number of events: adherence of LDL, monocytes, and platelets; secretion of chemokines and growth factors; production of ROS; impairing NO secretion; and so on. SRs, CD36, and LOX 1 help in the uptake of OX-LDL by monocyte-derived macrophages in the subendothelium. Growth factors mediate SMC proliferation and extracellular matrix formation. Platelet adherence and accumulation is also, in part elicited by Ox-LDL which results into a rupture prone thrombus.

Figure 7

Diagram illustrating the effects of diet, drugs, and genes on plasma LDL and coronary disease. The figure is reproduced from Goldstein and Brown [35] (under the Creative Commons Attribution License/public domain) “(Reprinted (A Century of Cholesterol and Coronaries: From Plaques to Genes to Statins) with permission from Elsevier (License number 4825791117921)).” (a) Diet. Idealized depiction of the frequency distribution of plasma cholesterol levels in the human species as extrapolated from surveys of middle-aged people in major populations of the world. The higher the cholesterol level, higher the risk for coronary disease, as denoted by graded red shading. (b) Drugs. Frequency of coronary events plotted against plasma level of LDL cholesterol in four double-blind, placebo-controlled trials in which middle-aged people at risk for heart attacks were treated for 5 years with a statin or placebo. The number of subjects in each study was as follows: 4S Study, 4,444; LIPID, 9,014; CARE, 4,159; and HPS, 20,536. (c) Genes. Difference in risk for coronary disease in middle-aged people depending on whether plasma LDL cholesterol level is reduced over a lifetime (heterozygous loss of function of PCSK9) or for only 5 years (statin therapy).

Figure 8

Hepatic responses to diet and statins mediated by the SREBP pathway. The figure is reproduced from Goldstein and Brown [35] [under the Creative Commons Attribution License/public domain] “(Reprinted (A Century of Cholesterol and Coronaries: From Plaques to Genes to Statins) with permission from Elsevier (License number 4825791117921)).” (a) Low-cholesterol diet. Proteolytic cleavage of SREBP is increased. The cleaved SREBP enters the nucleus to activate genes controlling cholesterol synthesis (including HMG CoA reductase) and uptake (LDL receptor). nSREBP, nuclear portion of cleaved SREBP. (b) High-cholesterol diet. Proteolytic cleavage of SREBPs is decreased, resulting in decreased nuclear SREBP and decreased activation of target genes. The decrease in LDL receptors produces an increase in plasma LDL. (c) High-cholesterol diet plus statin therapy. Statins inhibit HMG CoA reductase, causing a transient decrease in ER cholesterol. In response, SREBP cleavage is increased, and the resulting nuclear SREBP activates the genes for HMG CoA reductase and LDL receptor. The increased HMG CoA reductase is inhibited by the statin, and the increased LDL receptors lower plasma LDL.

Figure 9

Schematic representation of HDL countering major atherosclerotic stages. HDL counters significant stages of atherosclerosis. First, HDL retards the oxidation process of LDL and helps in the efflux of cholesterol form macrophages, preventing it from becoming foam cells. Cytokines and growth factors released by T lymphocytes and foam cells induce SMC migration and proliferation that is again countered by HDL. Additionally, platelet migration and aggregation is prevented to the site of plaque. Hence, high HDL is antiatherosclerotic and comes into play as soon as the LDL penetrates the dysfunctional endothelium.