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integration of its pathogenesis as a self-perpetuating propagating inflammation

a review

Poston, Robin N.

Cardiovascular Endocrinology & Metabolism: June 2019 - Volume 8 - Issue 2 - p 51–61
doi: 10.1097/XCE.0000000000000172

This review proposes that the development of the atherosclerotic plaque is critically dependent on its inflammatory components forming a self-perpetuating and propagating positive feedback loop. The components involved are: (1) LDL oxidation, (2) activation of the endothelium, (3) recruitment of inflammatory monocytes, (4) macrophage accumulation, which induces LDL oxidation, and (5) macrophage generation of inflammatory mediators, which also activate the endothelium. Through these stages, the positive feedback loop is formed, which generates and promotes expansion of the atherosclerotic process. To illustrate this dynamic of lesion development, the author previously produced a computer simulation, which allowed realistic modelling. This hypothesis on atherogenesis can explain the existence and characteristic focal morphology of the atherosclerotic plaque. Each of the components contributing to the feedback loop is discussed. Many of these components also contain subsidiary positive feedback loops, which could exacerbate the overall process.

Centre for Microvascular Research, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

Received 12 February 2019 Accepted 29 March 2019

Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website,

Correspondence to Robin N. Poston, MD, FRCPath, Centre for Microvascular Research, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK, e-mail:

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Atherosclerosis is the most important and well known disease of arteries which has a life-long and initially asymptomatic course. It finally gives rise to myocardial infarction, cerebrovascular accidents, and peripheral vascular disease. In its initial stages, it invariably has a characteristic focal plaque morphology that has not been explained (Fig. 1). Histology of the advanced lesion reveals a thickening of the intimal layer of the arterial wall by subendothelial collagen-secreting smooth muscle cells, which form a fibrous cap, masses of foamy macrophages, and extracellular cholesterol on its outer aspect. The current focus is how a little known dynamic property of the disease, its constitution as a positive feedback loop (+FBL) of damaging inflammatory processes, renders it self-perpetuating, and explains its existence and morphology. Some of the earliest evidence for the self-perpetuation of atherosclerosis came from attempts at regression in a rabbit model. After advanced lesions had been induced by cholesterol feeding, the animals were returned to a normal diet. Instead of regression, the lesions continued to accumulate cholesterol [1]. Even dietary restriction was ineffective [2].

Fig. 1

Fig. 1

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Atherosclerosis as a self-perpetuating propagating macrophage-dependent lesion

Macrophages are capable of oxidizing LDL [3], and much oxidized LDL (ox-LDL) is found within them in the lesions. Ox-LDL is an inflammatory mediator, which activates endothelial cells to allow a traffic of blood monocytes from the blood, which mature into macrophages. An association of the activation with the presence of macrophages in the plaque suggested to the author that these events could form a +FBL, in which macrophages produce ox-LDL and other mediators that could activate the endothelium to supply more macrophages, and strongly reinforce the development of the disease (Fig. 2).

Fig. 2

Fig. 2

A +FBL system in one in which the output is fed back to the input to enhance its size. It is a very powerful regulatory mechanism that can have dramatic effects. The explosion of an atomic bomb depends on the +FBL of energy-releasing neutrons rapidly releasing more neutrons in a critical mass of fissile plutonium. When present to a lesser extent, it greatly amplifies the change in the output of a system compared with the input.

When a +FBL system operates on a surface and has a property that spreads, local expanding or propagating changes can occur. An everyday example is the formation of rust spots in the paintwork of a car. Focal damage to the paint lets in water, rust formation follows, causing more damage to the paint, more water enters, and the rust spot expands. An elegant biological example is the conduction of the nervous impulse. A loss of electric potential across the nerve membrane opens channels which allow sodium ions to enter a nerve, the potential decreases further, and local electric currents are set up which spread the process along the nerve. The analysis of this process as a +FBL [4] was seminal to the application of the concept to atherosclerosis by the author.

To model the development of the atherosclerotic plaque as a macrophage-dependent self-perpetuating process, a computer simulation was used [5]. The view of the internal endothelial surface of an artery was represented on the computer screen (Fig. 3). At each pixel, the number of macrophages, smooth muscle cells, and quantity of extracellular lipid were variables. The probability of macrophage recruitment there from the blood was determined by another variable that was a function of the number of macrophages at that pixel or adjacent ones. Other probability functions controlled the death (loss) of macrophages, and the macrophage-dependent recruitment of smooth muscle cells. Dead macrophages contributed to a lipid pool. The functions were set arbitrarily and adjusted to give a realistic simulation. The simulation was run reiteratively, when at each cycle separate random number generations at each pixel determined the events there. Results for cells present were shown colour coded on the display screen (Fig. 3). A more realistic view of an artery as a 3D rendered tube was also provided. Lesions thickened the arterial wall in an inward direction, with a similar colour display on the inner surface. The video, Supplementary Digital Content 1,, shows the program running, in the simulated artery.

Fig. 3

Fig. 3

To achieve useful results, the probability function for macrophage recruitment had to have a very steeply rising value with macrophage numbers at a point, from a very small initial value in the absence of cells. Then, a realistic simulation of atherosclerosis was produced, with centrifugal expanding masses, first of macrophages resembling fatty streaks, and later like advanced lesions with central smooth muscle cells in a fibrous cap. Each time the simulation is run, it produces a different set of lesions, because of its dependence on random numbers. Finally, confluent lesions would develop.

Although this model provides a realistic representation of the atherosclerotic plaque, it is limited by the lack of any quantitative data for its generation. It does, however, support the hypothesis that self-perpetuating inflammation developing and spreading by a +FBL is a sufficient mechanism to explain the pathogenesis of the plaque. It also explains why its morphology is consistent, dependent on the +FBL, regardless of the nature of the inciting factor. This can be a localized flow disturbance or generalized risk factors such as hypercholesterolaemia or hypertension. Such processes trigger the mechanism, but have a lesser role during its evolution. Although amplified locally by a +FBL, the process operates slowly, as atherosclerosis develops over much of the lifetime of an individual, only having clinical effects in its final stages.

The individual atherogenic mechanisms which are involved in the +FBL will now be discussed, with the literature supplemented by the experience of the author, including some unpublished and unfunded work. Supplementary +FBL within the major loop will also be considered, all of which may increase the overall mechanism. Table 1 lists some of the +FBL mechanisms that may be involved.

Table 1

Table 1

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LDL oxidation

LDL enters the arterial wall relatively freely, recently discovered to be by transcytosis through endothelial cells via the scavenger receptor SR-B1 [45]. Interestingly, this is sensitive to oestrogen levels, thereby suggesting a mechanism for sex differences in the risk of atherosclerosis [46]. LDL entry may also be increased in regions with abnormal blood flow, through damage to endothelial cells, and promote disease at those sites [47]. It then becomes trapped in the intimal layer, due to the dense internal elastic lamina and media outside it [48].

LDL is an unstable molecule and spontaneously undergoes an oxidative degradation on storage, which is greatly accelerated by iron or copper ions. Therefore, this oxidation is likely to occur in LDL entrapped in the arterial intima. Moreover, both macrophages [49–51] and endothelial cells [52,53] can oxidize extracellular LDL, by membrane NADPH oxidase and 15-lipoxygenase. 15-Lipoxygenase is probably well expressed in fatty streaks [54], and less in advanced lesions [55], reports differ [56], but this difference correlates with the finding that lipid in early plaques may be enzyme oxidized, whereas that in advanced plaques is less so [55], again reports differ [57]. Macrophages also oxidize LDL intracellularly in lysosomes, contributing to cytokine release [58].

Oxidation renders LDL proinflammatory, provoking reactions analogous to a pathogen. It binds and activates many of the family of scavenger receptors, which interestingly are almost all bacterial receptors [59]. Oxidation initially modifies the surface phospholipids of the LDL particle, particularly phosphatidylcholine, in which arachidonic acid is usually present at the central sn2 position in the molecule [60]. This unsaturated fatty acid is readily oxidized, becomes more hydrophilic, and protrudes from the LDL particle like a whisker [61]. This part of the oxidized phospholipid formed is available for binding to receptors, unless removed by the lipoprotein phospholipase A2 enzyme (LpPLA2) [62] attached to the particle. A broad range of sn2 oxidation products in LDL are produced by the cellular oxidation [60], which give rise to the reactive inflammatory properties of ox-LDL, through binding to many cellular receptors. Those important here are CD36 and other scavenger receptors on macrophages, toll-like receptors (TLRs), and the scavenger receptor lectin-like oxidized LDL receptor-1 (LOX-1) on endothelial cells. The LpPLA2 gives rise to free fatty acid breakdown products, such as fatty acid hydroperoxides or short-chain fatty acid aldehydes, which are reactive, and can reattach to the LDL or other proteins. The remaining lysophospholipid with the fatty acid detached is biologically active, and in particular, can activate the endothelium through LOX-1 receptors [63]. Further prostanoid mediators are produced from arachidonic acid released by PLA2 from the LDL, or from intracellular arachidonic acid in macrophages.

It has been suggested that extracellular LDL might be modified in other ways to induce its uptake by macrophages and pathogenicity: binding to matrix components, desialation, formation of immune complexes [64], and aggregation by sphingomyelinase [65] have been implicated. A little known but potent mechanism for the modification and uptake of LDL is via group X secretory PLA2, which was reported in the plaque foam cells of mice [66]. Even native LDL can be taken up by pinocytosis [67]. Intracellular oxidation in lysosomes can follow [58]. A limited role for extracellular oxidation could help explain why human atherosclerosis does not respond to antioxidant therapies, but needs to be investigated further.

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Macrophages in the plaque

The response by macrophages to modified LDL is the driving force in atherogenesis, and the central theme of this review is that macrophage products form a major +FBL by activating the endothelium, or monocytes directly, to recruit more macrophages. Plaque macrophages are derived principally from monocytes that have transmigrated the luminal endothelium. However, when late lesions have undergone neovascularization of the intima, a massive new infiltration of monocyte/macrophages often develops. On the other hand, histological appearances usually suggest that there is a continual outward traffic through the intima of macrophages, which progressively enlarge into cholesterol laden foam cells. Unfortunately, there is no route for their exit from the lesions, except through the luminal endothelium, and their death from senescence, apoptosis, or necrosis follows. This results in the release of their cholesterol to form the characteristic extracellular deposits in the outer intima. There seems little room for efferocytosis, the phagocytosis of an apoptotic cell by a functional macrophage, to be important in this pathway, as it would only be passing the cholesterol buck from one cell to another. Some immediately subendothelial macrophages might reverse transmigrate the endothelium and leave the lesion, as the lesional endothelial cells have a high level of the junctional molecule JAM-C, which can enhance the process [68,69]. Nevertheless, it seems unlikely that they could carry any significant quantity of cholesterol, as lipid laden cells are not seen in reverse traffic in human.

Macrophages respond to their environment, are heterogenous, and were divided originally into M1 and M2, essentially proinflammatory and anti-inflammatory. These are involved in the initiation and resolution of inflammation, respectively [70]. However, classification has widened and includes Mox, a type induced by ox-LDL. These cells respond to oxidant stress through induction of the Nrf2 transcription factor, and importantly synthesize the COX-2 enzyme and secrete the inflammatory cytokine interleukin (IL)-1β [71]. Haem and haemoglobin from haemorrhages induce a further subtype, Mhem, which has antioxidant and protective properties [72]. A mixture of all these subtypes is present in plaques [71,73,74].

The unregulated uptake of ox-LDL by scavenger receptors results in the well known formation of foam cells: macrophages that are grossly enlarged by large quantities of cholesterol rich degradation products in their lysosomes [64]. CD36, a major scavenger receptor in human macrophages, has a PPARγ transcription factor sensitive element in its promoter that enhances its expression. Internalization of ox-LDL results in the generation of intracellular PPARγ ligands and its activation. The CD36 protein is upregulated, and in a +FBL, uptake of ox-LDL is greatly increased. A potential further +FBL, of PPARγ activating its own promoter via microRNAs, may enhance this effect [27,28,75]. In addition, the induction of tumour necrosis factor α (TNFα) in human macrophages by ox-LDL [21] increases NADPH oxidase levels [22], and this increases cellular oxidation of LDL [23]. Thus, yet another +FBL is formed! These mechanisms help explain the enormous accumulation of lipid in atheroma macrophages.

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Macrophage signalling

The macrophage mechanism for generating IL-1β on exposure to ox-LDL has recently developed clinical significance. In mice, ox-LDL internalized through CD36 is degraded, and the resulting cholesterol accumulating in lysosomes crystallises. These crystals destabilize the lysosomes, and contents are released. IL-1β is formed in intracytoplasmic molecular complexes, NLRP3 inflammasomes, which require two signals for their activation. The released lysosomal contents are the first, and the second is provided by the ox-LDL binding to CD36 located in a cell surface complex with TLR-4 and TLR-6. This operates through inflammatory signalling via reactive oxygen species (ROS) and NFκB [14,15,76]. Nrf2 is also essential [77]. The resultant potential inflammatory role of IL-1β in atherosclerosis has led to the large CANTOS phase III clinical trial with the human IL-1β mAb, canakinumab, for the secondary prevention of cardiovascular disease. In patients whose C-reactive protein (CRP) level fell below 2 mg/L, indicating an effective anti-inflammatory action, adverse events fell by 25%. In others, whose CRP did not fall, there was no benefit [78,79]. This trial result is important, as it is the first successful large-scale direct targeting of inflammatory mechanisms in the treatment of atherosclerosis.

A wide range of other cytokines have also been identified in plaques, and in macrophages stimulated by ox-LDL and its lipid components, particularly the chemokines CCL2 [16,17] and CCL5 [14,17], together with the IL-1α [18], IL-6 [14], IL-18 [19], and TNFα [20]. Even native LDL will induce IL-6 and TNFα from macrophages [80].

The plaque macrophages produce further inflammatory mediators. They contain the enzymes required for leukotriene synthesis, which include 5-lipoxygenase and leukotriene A4 (LTA4) hydrolase, and these are increased in lesions showing plaque instability [81,82]. Their products, LTB4, and the cysteinyl leukotrienes (cysLTs) LTC4, LTD4, and LTE4, are present in plaques [26]. 5-lipoxygenase has been implicated in mouse atherosclerosis, possibly through macrophage activation, as the knockout developed much less disease [26,83]. In addition to COX-2, plaque macrophages have a high level of thromboxane synthetase, and thromboxane A2 was shown to be produced by plaque tissue [24]. Furthermore, as atherosclerosis develops, macrophages in the plaques secrete high-mobility group box 1 (HMGB1) protein, a damage-associated molecular pattern molecule, which is a cytokine-like DNA binding protein, and is also released generally with cell necrosis [29]. Finally, and mainly separately from macrophages, cholesterol crystals [84] and another plaque lipid component [85] activate complement, and the activated inflammatory C5b-9 complex is deposited extensively [32].

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Endothelial inflammation and monocyte traffic

Here, endothelial inflammation will be outlined, and the mechanisms will be considered by which macrophage generated factors act on or near the endothelium to increase the entry of monocytes into the lesion, and complete the major +FBL.

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Endothelial dysfunction

There are gradated inflammatory changes in the endothelium with atherosclerotic disease. A major insight into generalized milder abnormalities of the vascular endothelium has been given by endothelial dysfunction. This can be measured clinically by the failure of the brachial artery to dilate on stimulation, due to inadequate production of nitric oxide [86]. This dysfunction is present with all the major risk factors for atherosclerosis, hyperlipoproteinemia [87], hypertension [88], smoking [89], diabetes [90,91], and obesity [92]. Multiple mechanisms contribute to the dysfunction in these systemic conditions [93–98], but there is a final common pathway of oxidant stress in endothelial cells, which results in lowered availability of nitric oxide, either through its neutralization by superoxide to give peroxynitrite, or by the uncoupling of the endothelial nitric oxide synthase enzyme so ROS are generated instead of nitric oxide [99].

Endothelial dysfunction is implicated in the atherogenic pathway, as it has a prognostic value in predicting cardiovascular events in hypertension [100], and in coronary disease itself [101]. It is a mild inflammation, as loss of nitric oxide represents loss of a normal anti-inflammatory activity [102].

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Plaque endothelium activation

The mechanisms by which inflammation of endothelial cells can give rise to a traffic of leukocytes across them have been well analysed [103,104], including in atherosclerosis [105,106]. In general, there are three stages, P- and E-selectin adhesion molecules on an activated endothelium catch leukocytes from the circulation, and allow them to roll along the endothelium, when then they come under the influence of activating chemokines, for example, CXCL1, bound to the glycocalyx on the membrane of the endothelial cells. Leuokocyte β2 and other integrin adhesion molecules consequently become activated, change conformation, and become capable of binding to endothelial molecules such as ICAM-1, which then arrest the leukocytes’ movement. In addition, monocytes adhere specifically to fibronectin which has been deposited onto α5β1 integrin [107]. Adherent cells then usually transmigrate through the intercellular junctions of the endothelial layer, under the guidance of junctional adhesion molecules [108]. Most of the analysis has been of neutrophil traffic in mice, but monocytes are largely similar, although they use some different molecules [106].

The mild generalized inflammation of endothelial dysfunction seems likely to increase the probability of low-level monocyte traffic, and the initiation of the +FBL phase of plaque generation at any site in the arterial tree. Above this background, there is a localized and more severe form of inflammation in the endothelium of plaques. This was first seen clearly in the locally increased levels of the adhesion molecules VCAM-1 in the endothelium of rabbit atherosclerosis [109], and of ICAM-1 [110] and P-selectin [111] in the human. In such regions, many monocytes can be seen adherent to the endothelium, or within the endothelial layer. VCAM-1 is also expressed in mouse atherosclerosis [112], and is involved in slow rolling and transition to static adhesion [106]. However, there is a difference in human: VCAM-1 was only detected in the luminal endothelium of 1/27 human plaques by avidin-biotin complex immunohistochemistry (Poston and Daw, unpublished results). Furthermore, no involvement of VCAM-1 was shown by antibody inhibition of monocyte adhesion to tissue sections of human plaques in vitro [113], despite positive results for P-selectin, β2 integrins, ICAM-1, and CD14.

Critical evidence for the importance of macrophages in +FBL plaque generation by induction of endothelial inflammation arose from detailed study of adhesion molecules in human plaques. In both the ICAM-1 [110] and P-selectin [111] endothelial expression studies, a subset of fibrous plaques lacked macrophages. They were often large, advanced and probably burnt out, and had much lower levels of endothelial adhesion molecules than other advanced plaques, for example, for P-selectin, 2.3% compared with 23.1% of the endothelium stained, P = 0.001. Furthermore, in greater than 100 areas of human plaques, the quantitative comparisons of the endothelial expression of either P-selectin, E-selectin, or ICAM-1 correlated significantly in almost all comparisons with the presence of macrophages in the subendothelial zone or the deep part of the intima (Poston and El-Dars, unpublished observations). This was despite the expression of E-selectin being very low. Similar results were reported by van der Wal et al. [114]. These observations together make a strong case that macrophages are driving the endothelial inflammation in human atherosclerosis, causing monocyte/macrophage traffic, and hence for self-perpetuating +FBL growth of the plaque.

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Inflammatory mediators

It is important to know which mediators can act on the endothelium. Ox-LDL is itself a candidate. One scavenger receptor, LOX-1, is expressed on endothelial cells. It binds ox-LDL, its component lysophosphatidylcholine, and many other LDL oxidation products [115]. It is found on the luminal endothelium of early human plaques, and in neovessels of advanced lesions [116]. Ox-LDL binding to LOX-1 stimulates adhesion molecule expression [117]. Furthermore, LOX-1, on binding to ox-LDL, upregulates its own expression [10]. There are two nested signalling +FBLs that probably explain this finding [11,12]. Despite these potentially highly stimulatory mechanisms, the effects of ox-LDL induced LOX-1 activation on endothelial adhesion molecule expression in vitro appear modest [117], and its expression in atherosclerotic endothelium is not universal [116]. However, as it also has a direct role in endothelial cell signalling for monocyte adhesion ([118] and see below), it must be an important molecule in atherogenesis, and a potential drug target [115].

Ox-LDL itself has a direct ability to induce monocyte adhesion under static conditions that has not been fully investigated. This may operate through a TLR4/CD14 receptor complex, and provides an explanation for the potent ability of CD14 antibodies in vitro to block monocyte adhesion to sections of atherosclerotic plaques [113,119]. Heat shock protein 60, a stress-related molecule that is expressed in the endothelial cells of human plaques, has a similar activity [119].

The wide range of oxidized phospholipids generated in ox-LDL has both proinflammatory and anti-inflammatory actions. Oxidation products from palmitoyl-arachidonoyl-phosphatidylcholine (PAPC) have been studied in detail [60,120,121]. In ox-LDL, the inflammatory monocyte binding effects predominate, as found with the 5-oxovaleroyl sn2 fatty acid derivative [122]. Similarly, in endothelial cells, an activating signalling pathway from G coupled protein membrane receptors is induced [13]. This results in connecting segment-1 containing fibronectin deposition on α5β1 integrin, leading to monocyte adhesion [13]. Interestingly, generalized inflammation and the recruitment of neutrophils does not follow, as the cAMP induced inhibits NFκB, and E-selectin and VCAM-1 are not increased [60]. This inhibitory action could explain the low expression of VCAM-1 and the very small recruitment of neutrophils into human plaques. Ox-PAPC also stimulates the formation of CCL2, CXCL1, CXCL3, and CXCL8 chemokines in endothelial cells, all of which enhance monocyte adhesion and traffic [60].

Lysophosphatidic acid (LPA) is a further derivative of lysophosphatidylcholine. It is found in lipid from human plaques, and is generated by a phospholipase D enzyme, autotaxin, which removes the choline headgroup. It induces monocyte adhesion when applied to mouse arteries, and CXCL1 in mouse endothelial cells. Genome wide association studies show a polymorphism of a degradative enzyme that affects the risk of the human coronary artery disease [123], suggesting that its role extends to humans.

Of the cytokines produced in plaque macrophages, IL-1α and β, IL-18 [19], and TNFα have the ability to stimulate the endothelium to produce adhesion molecules and chemokines, but the importance of these potential interactions is not known. IL-1 and IL-6 can amplify their own production by autocrine +FBLs in human endothelial cells [124,125]. Concerning other mediators, thromboxane activates endothelial cells to express adhesion molecules [25], while HMGB1 operates in a strong +FBL, in which it induces inflammation in endothelial cells and activates NFκB and Sp1 transcription factors [29,30]. It thereby increases both its own receptors, the receptor for advanced glycation end products and TLR-4, and its own secretion [31].

Deposition of the complement C5b-9 complex on endothelial cells has a major activating effect, with surface expression of P-selectin, and production of multiple cytokines [32], so is very likely to incite monocyte adhesion. Furthermore, C5a is both chemotactic for monocytes, and induces their endothelial adhesion [33]: it also activates P-selectin on endothelial cells [34]. Importantly, subendothelial complement and lipid deposition were seen together as early as two weeks after starting lipid feeding to rabbits, suggesting a role in lesion initiation [35].

A direct and important +FBL is that monocytes enhance their own adhesion to endothelial cells [36]. They produce IL-1 and TNF [126], and raise the endothelial cell expression of adhesion molecules [37,126]. This enhances their own migration and that of lymphocytes [126]. Elegant analysis by Sakamoto et al. [118] showed that endothelial LOX-1 was required, and that it activated NADPH oxidase, ROS generation, and calcium signalling. The co-traffic of lymphocytes is mainly of the TH1 type, which produce interferon γ and exacerbate the disease, particularly by activating macrophages and reducing collagen synthesis [127].

The formation of a fibrous cap of smooth muscle cells to a plaque may not always be stabilizing. In coculture experiments, the secretion of transforming factor β1 by smooth muscle cells greatly enhanced monocyte adhesion to endothelial cells, with their sensitivity to TNFα being increased 10 000 times [128].

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Classically, thrombosis is induced by endothelial disruption, either by metalloproteinase degradation of the intimal matrix in unstable plaques [129], or by endothelial erosion [130]. Platelets are thereby exposed to von-Willebrand factor (vWF) adherent to the matrix: rolling, activation, and tight adhesion via platelet αIIb/β3 integrin and collagen receptors follows [131,132]. However, there are activating factors from plaques that have had less consideration. Ox-LDL activates platelets through their scavenger [133] and platelet activating factor receptors [134], and thromboxane A2 is produced in plaque macrophages [24]. LPA likewise activates and aggregates them [135]. Moreover, platelets could potentially be activated on intact endothelium via vWF release from its Weibel Palade bodies. There are multiple mediators, such as TNFα [20], in plaques that have release ability [136–138].

The ability of platelets to self-perpetuate and spread their own activation rapidly, resulting in thrombus formation, is well known, and a good example of a spreading +FBL mechanism. Platelets on stimulation release thromboxane A2 and ADP [38], which bind to their TPα/β and P2Y1 / P2Y12 receptors, respectively, and activate surrounding platelets [39]. They also activate their αIIb/β3 integrin receptors, enabling cross linking through fibrinogen [40].

Coagulation coactivates with platelets in thrombosis, with stimulation from tissue factor (TF), much of which is produced by plaque macrophages. Either endothelial cells or platelets on activation provide a phosphatidylserine-rich surface on which the thrombin containing activating enzyme complex can assemble [40]. TF activates factors VII and X via the extrinsic pathway to initiate thrombin generation from prothrombin. Then, in a +FBL mechanism, thrombin activates XI, V, and VIII of the intrinsic pathway and self-perpetuates its own production [41]. Thrombin converts fibrinogen to fibrin, and has a potent stimulatory effect on platelets via protease-activated receptor receptors required for their full activation [40]. Likewise, it stimulates endothelial cells to enhance monocyte and platelet adhesion, the latter via release of vWF [139].

There are feedbacks also by platelets activating endothelial cells through phosphatidylserine binding to LOX-1 [42], CD40 binding to CD40 ligand [43], and through their release of thrombospondin [140]. The endothelial cells then express adhesion molecules and CCL2, aiding monocyte traffic into the lesion. In addition, platelet CCL5 and CXCL4 chemokines are released and deposited on the endothelium, further enhancing leukocyte interactions [141]. When platelets are activated in the presence of leukocytes, as in a thrombus, they can produce cysLTs by transcellular synthesis from LTA4 released by these cells. These have a potent ability to release vWF, P-selectin, and platelet activating factor from cultured endothelial cells [44], suggesting an important +FBL.

Understandably, these powerful propagating mechanisms are under multiple regulatory controls, which stabilize the normal state. This is particularly important at the endothelium, where nitric oxide, prostacyclin, and the cyclic nuleotidase CD39 inhibit platelet activation [132]. Similarly, thrombomodulin binds thrombin to disable its proteolytic action, and allows it to activate protein C. The activated protein C produced inhibits the coagulation pathway [41].

Thrombosis does not always result in occlusive arterial disease, but may be limited to adherent mass adding to the thickness of an atherosclerotic plaque, a mural thrombus. This can become incorporated into the plaque by the gradual replacement of its constituents by smooth muscle cells and macrophages, together with the formation of a new luminal endothelium. In this way, the plaque can increase greatly in size, particularly when already advanced, thereby adding to its +FBL growth.

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It is remarkable how many +FBL mechanisms can be implicated in the pathogenesis of atherosclerosis: this must relate to the importance to normal physiology of generating maximal inflammatory and haemostatic responses on demand through the amplification of signals provided by the +FBLs. Their appearance in atherosclerosis results from the persistent inappropriate signal from ox-LDL. Analysis of the components shows that there are potent mechanisms, many of themselves including +FBLs, which can assemble together to produce the major +FBL of the disease. This information supports the hypothesis that this major +FBL is critical to the development of the focal atherosclerotic plaque, and explains its morphology. The subloops help to produce the very large amplification that was demonstrated in the model to be necessary for plaque development. Understanding of the major loop components is variable: in particular little is known about the relative significance of the various signals from macrophages that could activate the endothelium: more is needed to confirm the hypothesis.

The +FBL mechanism is relevant to therapy, as agents affecting the major loop would benefit from an amplification of their inhibitory effect, just as with a positive signal. Statins are one example, as their ability to inhibit endothelial activation via prevention of G protein prenylation [142] targets a critical node in the pathway. The major +FBL could be investigated in an atherosclerosis model by applying an inhibitor such as a statin, and observing the chronological change in the level of plaque inflammatory mediators.

Finally, this review has attempted to cover the enormous amount of literature on the positive inflammatory aspects of atherosclerosis: parts may be missing. A further important stage will be to consider the negative regulation of these mechanisms. To keep abreast of such fields, databases with artificial intelligence capable of basic understanding of biological processes could be valuable.

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I thank Professor Vitaly Volpert, Editor-in-chief, Mathematical Modelling of Natural Phenomena, for permission to incorporate the video attached, Dr. John McGregor for helpful discussion, Dr. Patrick Salt for help in the initiation of the positive feedback hypothesis, and my son David Poston for writing the computer simulation of atherogenesis. The text of the review is original and has not been presented previously, the work discussed is either cited, or if described as unpublished, has not been presented previously.

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Conflicts of interest

There are no conflicts of interest.

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adhesion molecule; atherosclerosis; dynamics; endothelium; inflammation; inflammatory mediator; low density lipoprotein; macrophage; oxidation; atherosclerotic plaque; positive feedback

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