The cell proliferation and death are key processes in the progression of atherosclerosis and severe oxidative stress can cause cell death and even mild oxidation can trigger cellular stress and apoptosis, while more intense stress may cause necrosis [ 25 ].
There is a constant production of ROS and other oxidative species derived from the normal and xenobiotic metabolism, ionizing radiation and smoke snuff exposure, among others. Oxidative molecules can exert positive or negative effects over cells and tissues, depending on their concentration. ROS plays an important role in several physiological cell processes, such as signaling and regulation cascades, however excesses can induce chemical and structural modifications which has been proven that alter the function of cellular components, inhibit protein function, induce DNA damage, viral activation and lipid peroxidation which can promote cell death Figure 1.
In addition, redox systems such as gluthation peroxidase, thioredoxine reductase and pyridine nucleotide redox status can change their physiological function when modified by ROS and others reactive species, affecting the normal cell signaling including apoptotic cell death [ 26 ].
The figure shows some sources and consequences of oxidative stress. Today there are clear proofs that LDL oxidation plays a significant role in atherogenesis. In fact, this has been demonstrated throughout time. So, between and , 62 papers about OxLDL were published; between and January , the number of publications related to OxLDL went up to , and up to day only considering PubMed entry, it is possible to find over publications associated with the key words Oxidized LDL.
This growing interest is supported by the large amount of evidence which confirms that oxidative modification of LDL plays a pivotal role in atherosclerosis and hence, makes it an obvious target for therapeutic approaches [ 10 , 27 ]. In , Friedman et al. Specifically, polyunsaturated fatty acids PUFA either free or bound to an ester from phospholipid are converted into hydroperoxides, which break down to form highly reactive molecules, such as malondialdehyde and 4-hydroxynonenal among other metabolic products.
These reactive aldehydes can then form Schiff-bases, covalent Michael-type adducts with lysine residues of apolipoprotein B in LDL molecules. Besides, the sn-2 oxidized fatty acid fragments which can remain attached via ester bridges may also contain terminal reactive aldehydes.
However, this reactive phospholipid also called "aldehyde phospholipid core" may also form adducts with Schiff-base lysine residues of apolipoprotein B and presumably also with other proteins and amines-containing phospholipids, such as phosphatidylethanolamine and phosphatidylserine Figure 2.
Finally, the authors proved that when LDL presents substantial oxidative modifications, a great number of neoepitopes are generated transforming it in a highly immunogenic LDL. Indeed, there are a variety of autoantibodies directed to epitopes of OxLDL derived from specific oxidation in animals and human, that appear to increase in individuals with clinical and morphological signs of atherosclerosis [ 28 ].
Oxidative modifications in ApoB present in lipoproteins. On the contrary, OxLDL is thought to promote atherosclerosis through complex inflammatory and immunologic mechanisms that lead to lipid dysregulation and foam cell formation. In human beings it has been widely reported the presence of IgG anti-Ox - LDL antibodies, but their clinical significance is not clear yet [ 29 ]. The Acetyl LDL receptor, present in macrophages, uptakes the OxLDL much faster than the native receptors, favoring the excessive intracellular accumulation of cholesterol.
LDL oxidative modification, produces numerous structural changes, resulting in an increment of electrophoretic mobility, higher density, a polipoprotein B degradation, hydrolysis of phosphatidylcholine, changes on the amino groups of lysine residues and generation of fluorescent adducts caused by the covalent binding of lipid oxidation products to Apo B[ 31 ].
In vitro assays have shown that oxidative modification of LDL can be mutated by cultured endothelial cells or by cupric ions, which results in an increase of the lipoprotein uptake into macrophages [ 32 , 33 ]. Therefore, it seems to be obvious that LDL oxidation is a crucial step for macrophage-derived foam cells formation in early stages of an atherosclerotic lesion.
Moreover, LDL can be oxidized by specific enzymes such as lipooxygenase and phopholipase A2, even when these modifications are not necessarily identical to the endothelial cells-dependent modifications, they are still useful for studying oxidative alterations of LDL. In fact, in , it was demonstrated that the oxidative modification of LDL by specific enzymes leads to an increased recognition by macrophages [ 32 ].
In conclusion, it is possible to say that oxidation of LDL in cells depends on at least three possibilities: a lipid oxidation by the action of lipoxygenase within the cells followed by the LDL exchange on its medium; b direct lipoxygenase-dependent lipid oxidation during cell contact with LDL and c both possibilities mentioned above [ 34 ]. It is has been reported that the in vitro addition of acetyl groups to LDL acetylation , generates a modified LDL which can induce cholesterol accumulation in macrophages.
Thus, acetylated LDL increases the formation of foam cells [ 35 ]. Another process that needs to be taken into account is the autoxidation of glucose or the early glycation products carbonyl compounds generated by oxygen free radicals superoxide and hydroxyl and hydrogen peroxide that can cause oxidative damage.
Modifications of lipoproteins by glycation and oxidation alter their structure to make them sufficiently immunogenic. Immunogenic properties of glycosilated-OxLDL induce immune complex formation. It has been shown that glycosilated-OxLDL is trapped in the artery wall in situ [ 36 - 40 ]. A better understanding of redox control over the development of apoptotic process in the cell, could better guide the course of the therapeutic strategies associated with disorders related to oxidative stress [ 25 ].
A great number of diseases have been related to oxidative stress and generation of free radicals, for this reason, antioxidant therapies and diets such as Mediterranean diet rich or enriched with antioxidants are thought to be a promising way to prevent or at least to attenuate the organic deterioration originated by the excessive oxidative stress. Atherosclerosis is a chronic inflammatory disease of the arterial wall that culminates with the atheromatous plaque formation.
At present, there is a consensus that oxidation of LDL in the endothelial wall is an early event in atherosclerosis, according to the oxidative hypothesis [ 24 ]. First, the circulating LDL particles are transported from the vascular space into the arterial wall, mainly across trancytosis[ 41 ]. LDL is retained in the extracellular matrix of subendothelial space, through the binding of basic aminoacids in a polipoprotein B to negatively charged sulphate groups of proteoglycans in the extracellular matrix ECM [ 42 , 43 ], where it is prone to be oxidized by oxidative stress, generating OxLDL[ 21 ], as we previously mentioned in this article.
It is known that OxLDL participates actively in atheromatous plaque formation, where it is retained. Multiple studies provide evidence suggesting OxLDL contribute in atherosclerotic plaque formation in several ways.
In fact, at least four mechanisms have been proposed, being they complementary to each other: a endothelial dysfunction, b foam cell formation, c SMCs migration and proliferation and c induction of platelet adhesion and aggregation. The Endothelial dysfunction is a pathological condition in which the endothelium presents an impairment of anti-inflammatory, anti-coagulant and vascular regulatory properties.
Nowadays, it is considered a key event in the atherosclerosis development. OxLDL formed and retained in the sub-entothelial space, activates endothelial cells ECs through the induction of the cell surface adhesion molecules which in turn, induce the rolling and adhesion of blood monocytes and T cells.
Moreover, a clinically relevant protective impact of HDL-C has been challenged by randomised trials that failed to show a reduction in clinical events with agents that raise plasma levels of HDL-C [13].
Lp a is an LDL particle composed of an apo a component linked to apoB, and mainly carries cholesteryl esters and oxidised phospholipids. Moreover, Lp a exerts pro-coagulant properties as its structure resembles that of plasminogen, and it also has pro-inflammatory effects probably related to the oxidised phospholipid load [14].
Mendelian randomisation studies have shown a strong causal association between lifelong exposure to high Lp a levels and the risk of ASCVD [15].
Moreover, it appears that large absolute reductions in Lp a may be needed to achieve a clinically relevant reduction in ASCVD risk. In accordance with the evidence summarised above, LDL-C measurement is recommended class I recommendation as the primary lipid analysis method for screening, diagnosis, and management in current European dyslipidaemia guidelines [17]. Early statin trials comparing statin treatment of moderate intensity versus no treatment were able to show significant reduction in cardiovascular morbidity and mortality [3].
Later studies that compared more intensive versus less intensive statin treatment showed that a more aggressive LDL-lowering approach led to further reduction of major ASCVD events [1,3].
More recently, add-on treatment with non-statin medications ezetimibe or PCSK9 inhibitors on the background of statin therapy produced incremental reductions in cardiovascular morbidity as compared with optimised, intensive statin therapy alone [4,10].
In these trials, no level of LDL-C below which benefit ceases was identified, and no offsetting safety concerns emerged. Along the same lines, genetic studies showed that mutations leading to very low lifelong LDL-C levels such as, for example, loss-of-function mutations of the PCSK9 enzyme are associated with a very low incidence of ischaemic heart disease [1]. The goal-oriented approach advocates a tailored treatment with adjustment of drug dose or with a combination of lipid-modifying drugs, if applicable , aiming to reach the applicable LDL-C goal in each patient.
Advantages of this approach include a more specific, individualised treatment for LDL-C lowering and CV risk reduction also accounting for substantial inter-individual variability in treatment response to LDL-C lowering drugs , better patient—physician communication, and possibly better adherence to recommended treatment. Treatment goals are defined for each CV risk category, as summarised in Table 2 below.
Table 2. The recommendations regarding target goals for LDL-C are based upon the principle that decreasing the concentration of apoB-containing lipoproteins in the circulation decreases the probability that they will enter and become retained in the subendothelium.
Dr Konstantinos C. Our mission: To reduce the burden of cardiovascular disease. Help centre. All rights reserved. Did you know that your browser is out of date? To get the best experience using our website we recommend that you upgrade to a newer version. Learn more. Show navigation Hide navigation.
Sub menu. What is the role of lipids in atherosclerosis and how low should we decrease lipid levels? Konstantinos C. This is an open-access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Atherosclerosis, hardening of the arteries, is the leading cause of death in the United States, and worldwide. The disease triggers heart attack or stroke, with total annual death of , in the United States [1] and 13 million worldwide [2].
Atherosclerosis is a disease in which a plaque builds up inside the arteries. The plaque constricts the lumen of the blood vessel thereby increasing the shear force of blood flow [3] , [4].
As the plaque continues to grow, the increased shear force may cause rupture of the plaque, possibly resulting in the formation of thrombus blood clot [3] , [5] , ischemic stroke, and heart attack [3] — [5]. FRs are oxidative agents continuously released by bio-chemical reactions within the body, including the intima [6] — [8]. Endothelial cells, sensing the presence of ox-LDL, secrete monocyte chemoattractant protein MPC-1 [9] , [10] , which triggers recruitment of monocytes into the intima [11].
After entering the intima, monocytes differentiate into macrophages, which have an affinity for the ox-LDL [12] — [14]. The ingestion of large amounts of ox-LDL transforms the fatty macrophages into foam cells [12] , [15].
Foam cells secrete chemokines which attract more macrophages [10] , [12] , [13]. Interleukin IL, secreted by macrophages and foam cells [10] , [12] , [20] , contribute to the growth of a plaque by activating T cells [9] , [20] , [21]. At the same time that LDL enters the intima, high density lipoprotein HDL also enters into the intima, and becomes oxidized by free radicals [7] , [8].
HDL helps prevent atherosclerosis by removing cholesterol from foam cells, and by the limiting inflammatory processes that underline atherosclerosis [23].
Some of the key players in the atherosclerosis process are shown in Fig. Monocytes differentiate into macrophages which endocytose ox-LDL and become foam cells. SMCs are attracted from the media into intima by chemotaxis and haptotaxis.
Cytokines released by macrophages, foam cells and SMCs activate T cells. T cells enhance activation of macrophages. HDL helps prevent atherosclerosis. It has long been recognized that the cholesterol concentrations in the blood are indicators of the probability that a plaque will develop: higher LDL and lower HDL concentrations indicate a higher probability of plaque development.
Public health guidelines in the U. However, what is more relevant is to specify the risk associated with combined levels of LDL and HDL, and this is what the present paper addresses. A schematic of the network of atherosclerosis is given in Fig.
In this paper, we developed a mathematical model of plaque formation by a system of partial differential equations based on Fig. Anti-cholesterol drugs are aimed at lowering high levels of LDL, but some drugs are known to also increase the level of HDL [24]. Hence such a risk-map may be important when evaluating the extend to which an anti-cholesterol drug can reduce the risk of atherosclerosis for particular individuals. Ox-LDL recruits macrophages to intima. By ingesting ox-LDL, macrophages are transformed to foam cells.
In this paper, we present a mathematical model based on the network shown in Fig. The model includes the variables listed in Table 1.
We assume that all cells are moving with a common velocity u ; the velocity is the result of movement of macrophages, T cells and SMCs into the intima. We also assume that all species are diffusing with appropriate diffusion coefficients. The equation for each species of cells X has a form where the expression on the left-hand side includes advection and diffusion, and F X accounts for various growth factors, bio-chemical reactions, chemotaxis and haptotaxis.
The equation for the chemical species are the same but without the advection term. The distribution of LDL, HDL, ox-LDL and free radicals in the intima are described using reaction-diffusion equations [7] , 1 2 3 4 where k L and k H are reaction rates of oxidization, and is the reduction rate of ox-LDL due to ingestion by macrophages.
Equation 3 models the production of ox-LDL due to LDL oxidation by reaction with the radicals first term on right-hand side and a reduction of ox-LDL through ingestion by macrophages second term on right-hand side.
Equation 4 models the evolution of free radicals concentration with baseline growth r 0. The MCP-1 equation is given by 6 where the first term on the right-hand side is the production of MCP-1 by endothelial cells, whose density is assumed to be constant, under the influence of ox-LDL [9].
However, because of lack of experimental data, we do not include the IL-1 and IL-6 explicitly but instead consider their effect implicitly in estimating the parameter. For simplicity, we include the anti-inflammatory effect of IL produced by macrophages only implicitly, by the factor. The production of I 12 by macrophages is resisted by I 10 which, for simplicity, is accounted by the factor [10] , [12]. The second term represents the production of I 12 by foam cells [20].
Macrophages that have ingested a large amount of ox-LDL become foam cells [7] , [12] , [15] , so we have We assume that the intima has the constituency of a porous medium. This constant should be smaller than the average density of a plaque, 1. By adding Eqs. Then the equation of the density of ECM is given by 19 Since this equation can be written in the form where For simplicity, we consider only 2-dimensional plaques as in Fig.
The coefficient is a constant except for M , and , since ox-LDL attracts monocytes [11] , while HDL limits the inflammation process [23]. Note that L 0 and H 0 are the LDL and HDL concentrations in the blood, so we shall be interested to see how these concentrations determine whether a small plaque will grow or shrink.
Table 2 lists the range of molecular weights of proteins and Table 3 lists their range of concentration. In the second columns in Tables 2 and 3 , we indicate the intermediate values used in the simulations.
The Tables 2 and 3 are used to estimate some of the model parameters. A summary of all the model parameters is given in Tables 4 and 5.
It was estimated in [34] , that , and , so that their ratio is Accordingly, the corresponding reaction rates of the oxidation, k L and k H , are related by. In order to estimate the diffusion coefficients of the various proteins, we assume that the diffusion coefficient of protein p , D p , is proportional to its area A p , i.
Free radicals are monomeric globular proteins average weight is da, Table 2. We assume that, in Eq. In wound healing, macrophages produce PDGF at rate of 5. Since the plaque formation is a much slower process, we take this rate to be much smaller, i.
We assume that the production rate of MCP-1 by endothelial cells, , is twice that of , where is the concentration of MCP in the blood, which is equal to [44]. Accordingly, we derive the binding rate per Molar per second by same formula as in [44] , and where N A is called the Avogadro number, and is the number of molecular per dm 3. The range of macrophages in the blood is [75] ; we take.
The study also found that a second protein called dedicator of cytokinesis 4, or DOCK4, partners with SR-B1 and is necessary for the process. In the early stages of atherosclerosis, LDL that has entered the artery wall attracts and is engulfed by important immune system cells called macrophages that ingest, or "eat," LDL particles. LDL-laden macrophages become foam cells that promote inflammation and further the development of atherosclerotic plaques.
The plaques narrow the artery and can become unstable. Plaques that rupture can activate blood clotting and block blood flow to the brain or heart, resulting in a stroke or heart attack. In studies of mice with elevated cholesterol, the investigators determined that deleting SR-B1 from the endothelial cells lining blood vessels resulted in far less LDL entering the artery wall, fewer foam cells formed, and atherosclerotic plaques that were considerably smaller.
In their studies, the researchers compared SR-B1 and DOCK4 abundance in areas of the mouse aorta that are prone to plaque formation compared with regions less likely to become atherosclerotic.
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