Pathogenesis of atherosclerosis
Inception of the plaque
Atherosclerosis derives from the Greek word for “gruel” or “porridge”, demonstrating the manifestation of the lipid material found in the core of the typical atherosclerotic plague [7]. Though the exact initiator of atherosclerotic plaque formation is still debatable, there is a general consensus that the endothelial denuding injury, which could be triggered by multiple causes, such as smoking, hypertension, hyperglycaemia, immune injury, infection, sets a complex pathogenic sequence into motion [7–9]. From this point on, an inflammatory response leads to the development of the plaque. Endothelial cell dysfunction leads to platelet aggregation and release of platelet factors which subsequently recruit circulating monocytes from the blood into the intima, where they differentiate into macrophages and induce the proliferation of smooth muscle cells in an attempt to restore endothelial function. These cells will expand the extracellular matrix that would entrap and modify lipoproteins to become lipid‐rich foam cells, forming a fibromuscular plaque [7,8].
Endothelial dysfunction
Endothelium, the continuous cellular lining of the vascular system, is an essential part of critical regulatory nodes in the homeostatic network [8]. Endothelial denuding injury is well‐known to be an early and clinically relevant pathophysiologic event in the atherosclerotic process, a pivotal contributor to the local and systemic manifestations of atherosclerotic cardiovascular disease [10]. Endothelial dysfunction is more likely to occur at the arterial site that subjected to low shear stress and disturbed blood flow [11,12]. Acute inflammation involves the rapid recruitment of neutrophils and the stimulation of the endothelium, both type I and type II activation. Type 1 activation is independent of new genes expression, while type II activation is dependent on new genes expression with slower response [13]. Type I activation is of rapid onset, self‐limited and usually do not result in sustained morphological or functional changes. It is typically mediated by ligands that bind to a heterotrimeric G‐protein‐coupled receptor (GPCR), which triggers the release of Ca2+ ions from the endoplasmic reticulum (ER) leading to increased production of arachidonic acid [13]. Arachidonic acid is converted by cyclooxygenase‐1 (COX1) and prostacyclin synthase into prostaglandin I2 (PGI2), a potent vasodilator that relaxes vascular smooth muscle [14]. Elevated cytosolic Ca2+ ions also bind to the adaptor protein calmodulin and activates endothelial nitric oxide synthase (eNOS) producing NO, which has similar function with PGI2 [15]. The formation of Ca2+–calmodulin complex also leads to the phosphorylation of myosin light chain, which initiates contraction of actin filaments that are attached to tight junction and adherent junction proteins, resulting in the opening of gaps between adjacent endothelial cells, allowing leukocytes to cross through [15, 16]. Altogether, these pathways lead to increase blood flow including leucocyte delivery and enhance the leakiness of venules to the extracellular matrix, that supports the attachment, survival and extravasation of invading neutrophils [17,18].
Different to type II activation of endothelial cells, type I activation typically last for 10–20 minutes due to desensitisation of the receptors, which prevents the restimulation and limiting the degree of inflammation and neutrophil migration [19]. Activated leukocytes producing inflammatory cytokines such as interleukin‐1 (IIL‐1) and tumour necrosis factor α (TNFα), which are the key players in type II activation [13]. The binding of IL‐1 or TNFα to its respective receptors initiates various kinase cascades that lead to the activation of the transcription factor‐κβ (NF‐κβ) and activating protein 1 (AP1) [15]. These factors trigger the transcriptions of various nucleus genes leading to expression of proinflammatory proteins (E‐selectin, intercellular adhesion molecule 1 [ICAM1] and vascular cell‐adhesion molecule 1 [VCAM1]), chemokines (interleukin‐8 [IL‐8]), and enzymes (cyclooxygenase‐2 [COX2]) [15]. Hence, type II activation requires a longer time due to transcription and translation of new proteins [15]. Similar with type I activation, type II activation induce the leakage of plasma proteins and leukocyte recruitment with slightly different mechanism compared to type I activation. TNFα and IL‐1 stimulate venular endothelial cells to reorganise their actin and tubulin cytoskeletons and open up gaps between adjacent endothelial cells [20,21].
Historically, a critical link between the activations and arterial endothelial dysfunction in atherogenesis comes with the discovery of atherosclerosis‐associated VCAM‐1, which found to have selectivity adhesivity for mononuclear leukocytes and lymphocytes [22,23]. The dysfunctional endothelium overexpressed VCAM‐1 and ICAM‐1 on its surface, facilitates the adhesion and transendothelial migration of leukocytes [9]. Monocyte migration to extracellular matrix induces expression of various cytokines, such as TNFα, IL‐1, IL‐6, platelet‐derived endothelial cell growth factor, transforming growth factor (TGF)‐α and ‐β, and macrophage colony‐stimulating factor which is one of the key players in the differentiation process of monocytes to macrophages in the subendothelial space [9,24,25]. The macrophages ingest oxidised low‐density lipoprotein (LDL) via scavenger receptors, forming “foam” cells. Endothelial cells also produce MCP‐1, monocyte colony‐stimulating factor and IL‐6 which further amplify the inflammatory cascade [26]. IL‐6 production by smooth muscle cells represents the main stimulus for C‐reactive protein (CRP) production [27]. Recent evidence suggests that CRP may contribute to the proinflammatory state of the plaque both mediating monocytes recruitment and stimulating monocytes to release IL‐1, IL‐6, TNFα [28]. The damaged endothelium allows the passage of lipids into the subendothelial space. Fatty streaks represent the first step in the atherosclerotic process.
Cholesterol
LDL particles are well‐known as one of the critical players in the pathogenesis of atherosclerosis, however, the association of LDL amount can cause atherosclerosis remains unclear, even though lowering this lipoprotein reduces atherosclerosis‐related cardiovascular events [7, 29–31]. On the other hand, even though both LDL and high‐density lipoprotein (HDL) particles are highly heterogenous [32], plasma HDL‐cholesterol concentrations are negatively associated with atherosclerosis [29,33]. Interestingly, raising plasma HDL‐cholesterol concentrations did not show any benefit on existing atherosclerosis [34], which might suggest that HDL function may play a more pivotal part in the prevention against atherosclerosis by averting endothelial activation and enhance NO production []. LDL can deposit in the arterial wall due to impaired endothelial barrier function and retain within the intimal layer by extracellular matrix macromolecules [38]. Enormous researches demonstrated that the oxidisation of LDL particles including ROS formation in the intimal wall due to metal ion catalysis could initiate atherogenesis [39,40]. Oxidised LDL is the major modified form of native LDL since structurally it is very prone to oxidative damage [41]. The oxidised LDL particles serves as ligands for the scavenger receptors (SRs) that facilitate macrophage foam cell formation which is the hallmark of early atherosclerotic lesions that subsequently promoting humoral and adaptive immunity leading to plaque formation [7,42,43].
Oxidative stress
Since the 1950s, oxidative stress has a significant role in the pathogenesis of atherosclerosis, and the degree of oxidation correlates with the severity of the diseases [44]. Multiple reactive oxygen species (ROS) generator are present in the vascular wall, including the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, uncoupled endothelial nitric oxide synthase (eNOS), mitochondrial enzymes, and xanthine oxidase (XO), which develops a cross‐talk between the enzymes, creating a vicious cycle [5]. The function of the NADPH oxidase enzymes is to catalyse the one‐electron transfer from NADPH to molecular oxygen, thereby generating