Introduction

Cardiovascular diseases continue to be a predominant cause of mortality worldwide, and their prevalence is anticipated to increase in the forthcoming years [1]. In the fight against cardiovascular disease to reduce its effects on health outcomes, a crucial approach centers on implementing primary and secondary prevention strategies, along with effectively managing modifiable risk factors. One promising avenue deserving exploration is the role of oxidized low-density lipoproteins (Ox-LDLs), the primary component of plaque formation in atherosclerosis [2].

Atherosclerosis is a persistent inflammatory condition that significantly influences the emergence of cardiovascular diseases [3]. The idea that inflammation plays a crucial role in the development of atherosclerosis and its associated complications has attracted significant interest; however, it has not yet been integrated into clinical practice [4]. The hallmark of atherosclerosis is the buildup of Ox-LDL within the walls of arteries, which leads to plaque development [5]. Ox-LDL’s presence sets off an immune reaction that causes oxidative stress and inflammation in the arteries. Such stress harms the endothelial cells that line the blood vessels and leads to the attraction of white blood cells, which starts the creation of foam cells. These cells add to the growth and buildup of plaque. Consequently, the involved arteries lose flexibility and become narrow, which hinders the flow of blood to essential organs such as the heart and brain [6]. Without treatment, atherosclerosis may result in serious pathologic scenarios, including heart attacks and strokes. Hence, it’s vital to explore the role of Ox-LDL and comprehend the processes of Ox-LDL accumulation and oxidative stress to devise effective prevention or treatment methods for cardiovascular diseases. The discovery and categorization of different classes of scavenger receptors have shed light on their essential role in facilitating the uptake of Ox-LDL and the advancement of atherosclerosis [5, 7]. These receptors assume a critical function in the uptake of Ox-LDL by macrophages. This intricate process lies at the core of comprehending the genesis and progression of atherosclerosis.

LDLs: structure, biochemistry, and measurement

LDL serves as the primary transporter of cholesterol to cells. An increase in dietary fat contributes to its elevated levels, which can lead to pathological complications once a certain threshold is surpassed. LDL is part of a diverse group of particles, with a mass of approximately 3,000 kDa and a diameter of 220 nm. Its hydrophobic core consists of roughly 170 triglycerides and 1,500 cholesterol esters, while its hydrophilic surface is formed by around 700 phospholipid molecules, approximately 500 unesterified cholesterol molecules, and a single large molecule of ApoB weighing 500 kDa [8]. Numerous expert panels have concluded that the assessment of ApoB is sufficiently standardized for clinical practice. Furthermore, ApoB can be measured cost-effectively through commonly accessible automated techniques, offering greater accuracy, precision, and selectivity compared to LDL cholesterol or non-high-density lipoprotein cholesterol [9].

Oxidized low-density lipoproteins

Oxidation of LDLs, commonly known as the “bad cholesterol”, is intricately linked to the development of atherosclerosis. To comprehend the underlying mechanisms of this process, it is imperative to delve into the processes of modification and internalization of these particles. The LDL receptor, commonly referred to as LDLR, serves as a receptor located on the cell surface that is crucial for the identification and uptake of native LDL (nLDL) particles (Figure 1). This receptor is primarily found in hepatocytes and is essential for the removal of circulating LDL from the bloodstream. The mechanism by which LDLR facilitates the endocytosis of nLDL involves the interaction of ApoB (ApoB100), which is the protein part of LDL, with the receptor. Following this interaction, nLDL is taken up via clathrin-coated pits and subsequently transported to endosomes [10]. In the endosomes, where the medium is acidic, the LDLR experiences conformational changes that facilitate the release of LDL from the complex of ligands and receptors. Subsequently, the liberated LDL is transported to lysosomes for degradation, resulting in the release of its content including the free cholesterol.

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Figure 1. 

Ox-LDL in atherosclerosis [5]. CE: cholesteryl esters; LDL: low-density lipoproteins; LDLR: LDL receptor; nLDL: native LDL; Ox-LDL: oxidized LDL; PL: phospholipids; TG: triglycerides; VLDL: very LDL

Note. Reprinted from “Scavenger receptors: different classes and their role in the uptake of oxidized low-density lipoproteins” by Babakr AT. Biomed Pharmacol J. 2024;17:699–712 (https://dx.doi.org/10.13005/bpj/2897). CC BY.

The regulation of LDLR expression is subject to feedback mechanisms, at equilibrium, the quantity of LDLRs is modulated to facilitate the uptake of adequate cholesterol necessary for cellular proliferation while also compensating for losses. This regulatory feedback is mediated by membrane-associated transcription factors referred to as sterol regulatory element binding proteins (SREBPs) [11]. In conditions of low cellular cholesterol levels, SREBP-2 becomes activated and moves to the nucleus, where it binds to the promoter region of the LDLR gene, initiating its transcription. This process results in an upsurge in LDLR expression, leading to increased uptake of circulating LDL. Conversely, high cellular cholesterol levels inhibit SREBP-2, causing a reduction in LDLR expression. This feedback mechanism plays a crucial role in maintaining cholesterol balance by decreasing LDL uptake when cellular cholesterol levels are adequate.

Factors such as inflammation, hyperglycemia, and a deficiency in dietary antioxidants can induce oxidative stress, which can subsequently lead to the oxidation of LDLs [12]. These altered lipoproteins are recognized by scavenger receptors, which are encoded by a specific group of genes. Clearance of Ox-LDL primarily occurs in macrophages, dendritic cells, and Kupffer cells in the liver. Nevertheless, scavenger receptors are also present in other cell types, including endothelial cells [13, 14]. If the efficient degradation of Ox-LDL is impeded and scavenger receptor expression is unregulated, it can result in cellular dysfunction, apoptosis, and the formation of foam cells [15]. The wide array of diseases linked to lipoprotein oxidation may have a common root cause. This underscores the significance of understanding the intricate interplay between LDLR regulation, oxidative stress, and scavenger receptor function in various pathologies [16].

Oxidation of LDL

It becomes evident that exploring how oxidative stress transforms nLDL particles into proatherogenic molecules is paramount in understanding atherosclerosis pathogenesis.

The oxidation of LDL is a critical step in the development and progression of atherosclerosis and many pathological conditions. A key statistic that highlights this importance is that Ox-LDL can induce endothelial dysfunction [17, 18], which is an early event in atherosclerosis. Endothelial dysfunction refers to impaired function of the cells lining blood vessels, leading to reduced vasodilation and increased inflammation. The oxidative modification leads to structural changes in LDL, making it more prone to uptake by macrophages [19, 20]. Once engulfed by macrophages, these Ox-LDL particles trigger an inflammatory response and contribute to foam cell formation, a hallmark feature of early atherosclerotic lesions. There are two forms of Ox-LDL: minimally modified and extensive Ox-LDLs. Both have been shown to contribute to the formation of fatty plaques in arteries. The physiological oxidizing agents responsible for this process remain an active area of research [21].

An increase in reactive oxygen species (ROS) production leads to the oxidation of various components of LDLs, such as phospholipids, cholesterol esters, and polyunsaturated fatty acids, culminating in the formation of Ox-LDLs. The oxidation of LDL is a complex, multi-step process. The initial phase, known as initiation, involves the attack of free radicals on the polyunsaturated fatty acids present in LDL particles, resulting in the generation of lipid peroxyl radicals, followed by the propagation phase, during which these radicals engage in further reactions with additional fatty acids, thereby instigating a chain reaction that leads to widespread lipid peroxidation. The process concludes with the termination phase, wherein antioxidants or other molecules neutralize the lipid radicals, effectively ceasing the oxidation process [8, 22]. In scenarios characterized by inadequate antioxidant defenses, Ox-LDL is recognized by macrophages, which subsequently leads to the formation of foam cells. Numerous investigations have employed in vitro-generated Ox-LDLs as a model for studying circulating Ox-LDLs in the context of atherosclerosis, and several chemically modified LDLs have been proposed to mimic Ox-LDLs [6]. While minimally modified LDL (mmLDL) do not exhibit strong binding affinity to macrophage scavenger receptors, they can enhance the expression of receptors such as CD36, SR-A, and macrosialin, mmLDLs arise from the oxidative modification of the lipid components of LDL, primarily phospholipids, without altering the apolipoprotein ApoB100. The oxidation of ApoB100 occurs at a later stage, resulting in the formation of highly Ox-LDLs [8, 23, 24].

Minimally modified LDL

mmLDL refers to the early stages of oxidation, where only small changes have occurred in the structure of LDL particles. These modifications can result from various physiological processes such as enzymatic or non-enzymatic reactions. Despite their relatively mild nature, these modifications are still recognized by specific receptors on macrophages, leading to the uptake of cholesterol and subsequent foam cell formation within arterial walls.

mmLDL plays a bio-vital role in atherosclerosis through various mechanisms and contributes to the initiation and propagation of this pathological process. One mechanism by which mmLDL promotes atherosclerosis is through its interaction with Ox-LDLRs on macrophages [25], leading to foam cell formation. In addition, previous works suggest that mmLDL can also bind to these receptors, albeit with lower affinity compared to fully Ox-LDL [26]. This binding triggers intracellular signaling pathways that promote inflammation and oxidative stress, further exacerbating endothelial dysfunction and promoting plaque formation. Moreover, mmLDL can undergo additional modifications within the arterial wall itself. Enzymes such as myeloperoxidase and lipoxygenases are present in abundance at sites of inflammation, where they catalyze the oxidation of mmLDL into extensive Ox-LDL, as described in Figure 2. The resulting Ox-LDL has been shown to be more pro-inflammatory and cytotoxic than mmLDL. Thus, while mmLDL serves as an initial trigger for atherosclerosis development, it can also serve as a precursor for the production of highly detrimental Ox-LDL species [27, 28].

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Figure 2. 

Native LDL, mmLDL, and Ox-LDL. Extensive Ox-LDL occurs when both lipids and the side chains of the ApoB protein are subjected to oxidation. The illustration was partially created utilizing Servier Medical Art, which is supplied by Servier and is licensed under a Creative Commons Attribution 4.0 unported license (https://creativecommons.org/licenses/by/4.0/)

In summary, mmLDL represents an important player in the pathogenesis of atherosclerosis. Its ability to interact with Ox-LDLRs on macrophages and induce inflammatory responses highlights its contribution to early lesion formation. Additionally, its susceptibility to further modification within the arterial wall underscores its strong association with the formation of extensive Ox-LDL species.

Extensively Ox-LDL

Extensively Ox-LDL is considered as the key player in the whole process of atherosclerosis [29]. Various mechanisms have been discovered that can result in the oxidation of LDL in the body. When LDLs undergo oxidation, both lipids and the side chains of the ApoB protein are subjected to oxidation through radical chain reactions [6]. Lipid oxidation products, which consist of reactive aldehydes, form covalent bonds with ApoB proteins to create adducts. The progression of atherosclerotic vascular disease and other pathologic scenarios such as type-2 diabetes [30, 31] may potentially be linked to Ox-LDL, as indicated by serum autoantibody levels, based on clinical and epidemiological research. Extensively Ox-LDL represents a more advanced stage of modification, characterized by multiple oxidative events that significantly alter its composition and function. This heavily oxidized form of LDL not only loses its ability to bind efficiently to normal LDLRs but also gains new properties that promote inflammation and endothelial dysfunction. As a result, extensive Ox-LDL becomes highly proatherogenic and immunogenic, contributing to plaque formation and progression [32]. LDLR is the primary receptor responsible for the uptake of nLDL by cells. However, when gets oxidized, nLDL will no longer be internalized by normal LDLR, in fact, they will be targets of the many scavenger receptors of macrophages. For example, unlike LDLR, the lectin-like Ox-LDLR-1 (LOX-1) is a major receptor in endothelial cells that recognizes and binds to Ox-LDL specifically [33]. The binding of Ox-LDL to LOX-1 triggers a cascade of cellular events, including the internalization of Ox-LDL, the generation of ROS, and the activation of inflammatory pathways.

In summary, the shift from minimally modified to extensively Ox-LDL marks a critical step in the scenario of atherosclerosis. The altered composition and function of extensive Ox-LDL make it a potent agent in promoting inflammation, endothelial dysfunction, and plaque formation. Understanding the precise physiological oxidizing agents that drive this process is essential for developing targeted therapeutic strategies to mitigate the impact of extensive Ox-LDL on cardiovascular health.

Scavenger receptors: role in atherosclerosis

Scavenger receptors play a significant role in atherosclerosis progression. These receptors of different classes are primarily expressed in macrophages and endothelial cells [5]. Their contribution to atherosclerotic scenarios involves a variety of processes as shown in Table 2 and Figure 3.

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Figure 3. 

Multiple roles of scavenger receptors in atherosclerosis

Scavenger receptors exhibit less selectivity and can bind other modified forms of lipoproteins [46]. These receptors are typically found on macrophages within arterial walls and contribute to foam cell formation, a hallmark characteristic of early lesions of atherosclerosis. One of the key roles of scavenger receptors is their ability to bind to a wide range of ligands and facilitate their removal.

The mechanisms through which scavenger receptors accomplish the clearance of different ligands involve processes such as phagocytosis, endocytosis, adhesion, and signaling [14]. Considerable efforts were made to discover innovative therapeutic approaches that can prevent or reverse the detrimental effects of cardiovascular disease by elucidating the complex interplay between oxidative stress, receptor function, and plaque formation. However, these efforts were hindered by many challenges including the poor knowledge regarding the structure, functionality, and mechanism of action of scavenger receptors. Therefore, further research and development of targeted interventions were strongly recommended for better outcomes in these pathologic conditions.

Conclusions

In conclusion, this review has explored the critical roles of Ox-LDLs in the pathogenesis of atherosclerosis, underscoring their involvement in foam cell formation, endothelial dysfunction, and inflammatory responses in the arterial walls. By examining the interactions between nLDL, Ox-LDL, and their respective receptors, as well as the pivotal function of scavenger receptors in the uptake of Ox-LDL, and the atherogenic effects of these receptors, the paper highlights the complex mechanisms driving atherosclerosis and its progression to cardiovascular diseases. Furthermore, the review emphasizes the importance of oxidative stress in transforming LDL into proatherogenic molecules and the transition from minimally modified to extensive Ox-LDL, which is crucial for disease development.

This review stresses the need for a deeper understanding of the interplay between oxidative stress, LDLR regulation, and scavenger receptor activity to identify potential therapeutic targets. Addressing these aspects through targeted interventions could mitigate the burden of cardiovascular diseases, which remain the leading cause of mortality and financial strain on healthcare systems worldwide. Finally, the challenges in utilizing Ox-LDL as a biomarker for clinical applications highlight an area needing further research, aiming to refine prevention and treatment strategies for atherosclerosis and associated cardiovascular conditions.