This AOP is licensed under the BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

AOP: 462


A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.  More help

Activation of reactive oxygen species leading the atherosclerosis

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Activation of ROS leading the atherosclerosis
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.5

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool


The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Hiromi Ohara 1, Shigeaki Ito 1

1 Japan Tobacco Inc. 6-2, Umegaoka, Aoba-ku, Yokohama, Kanagawa, 227-8512, Japan

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Hiromi Ohara   (email point of contact)


Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Hiromi Ohara
  • Shigeaki Ito
  • Kazushi Matsumura
  • Ayaka Hayashida
  • Akina Mori


This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on April 29, 2023 16:03

Revision dates for related pages

Page Revision Date/Time


A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

The pathogenesis of atherosclerosis is initiated by the production of reactive oxygen species (ROS: MIE), which elicit oxidative stress in the vasculature (KE1). Oxidative stress responses elicit further endothelial dysfunction (KE2). This impairs the endothelium readily causing the penetration of low-density lipoprotein (LDL) into the intima, which is directly oxidized by ROS, forming oxidized LDL (KE5). The impaired endothelium has an increased expression of adhesion molecules, which recruit blood monocytes, which adhere and then infiltrate into the intima region (KE3). The microenvironment of the impaired endothelium induces the differentiation of monocytes into macrophages (KE4). Macrophages in the intima uptake oxidized LDL intracellularly, forming foam cells (KE6) and the accumulation of lipid-rich foam cells and their debris after necrosis form plaques (i.e., lipid core, KE7)). These conditions promote the migration of fibroblasts and trans-differentiation of smooth muscle cells into myofibroblasts, which form a fibrous cap on the apical side of the plaque (KE7). Then, the increased expression of collagenase causes thinning of the fibrous cap by the degradation of collagen in the fibrous cap (KE8). These plaques are unstable and this eventually leads to rapture. The aggregation of platelets occurs around the raptured endothelium leading to the formation of three-dimensional clots (i.e. thrombosis, AO).

AOP Development Strategy


Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help


Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help


Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Life Stage Applicability

Age is a significant independent risk factor for CVD because it is associated with an increased likelihood of developing any number of other additional cardiac risk factors, including obesity and diabetes [1]. The prevalence of most types of CVDs is considerably higher among older adults compared with the general population [2]. An increase in the production of ROS occurs with advancing age [3, 4], and is linked to persistent inflammation and progression to chronic disease status. Therefore, conditions that induce ROS activation and result in thrombosis may be more applicable to adults.

Sex Applicability

Estrogen was shown to have a cardioprotective role and to be directly associated with a lower overall incidence of CVD in premenopausal women compared with age-matched men [5-7]. The decline of sex hormones has an important role in the development of CVD with advanced age, in men and women [6]. Therefore, ROS activation resulting in thrombosis may be moderate in premenopausal women.

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence for the essentiality of Key Events (KEs) has been confirmed mostly by the attenuation of KEs by inhibitory substances, targeted gene silencing. Attenuation of KEs by inhibitory substances and modification of target gene expression (i.e., knockdown, knockout, and overexpression). Rationale for essentiality includes:

Reactive oxygen species (ROS) lead to oxidative stress [High]

Reactive oxygen species (ROS) are a group of highly reactive molecules derived from O2 metabolism [8]. Members of the ROS family include superoxide (O2-), alkoxyl radical (RO-), peroxyl radical (ROO-), hydroxyl radical (OH-), peroxynitrate (ONOO-), hydrogen peroxide (H2O2), ozone (O3), and hypochlorous acid (HOCl). Although physiological concentrations of ROS are important signaling molecules that maintain vascular homeostasis, excessive ROS production can lead to oxidative stress and the progression of vascular disease. ROS maintain vascular cell homeostasis by regulating the phenotype and fate of multiple cell types, including endothelial cells (ECs), vascular smooth muscle cells (SMCs), outer membrane cells, bone marrow cells, and resident stem/progenitor cells [9, 10]. The administration of the antioxidant N-acetylcysteine, a known inhibitor of oxidative stress, reduced the severity of atherosclerosis [11].

Oxidative stress leads to endothelial dysfunction [High]

Endothelial dysfunction is considered an early indicator of atherosclerosis characterized by the overexpression of adhesion molecules including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) [12]. Extracellular as well as intracellular ROS functions as signaling molecules that, produced either intracellularly, extracellularly or through ligand-receptor interactions, function as signaling molecules that activate ICAM-1 and regulate immune cells migration through the vascular endothelium to sites of inflammation and injury [13].

Endothelial dysfunction leads to monocyte infiltration [Moderate]

Vascular endothelial functions are critical; thus, genetic modification to disrupt their function is lethal. Maintaining nitric oxide (NO) bioavailability is one of the key functions of the vascular endothelium and is achieved by the expression of endothelial NO synthase (eNOS). The overexpression of eNOS in a diet-induced atherosclerosis model resulted in a significant reduction in atherosclerotic lesions [14]. Monocyte infiltration is associated with the induction of ICAM-1 on the endothelial cell surface, which captures circulating blood monocytes. A deficiency of ICAM-1 in apolipoprotein E deficient mice significantly reduced atherosclerotic lesions [15].

Monocyte infiltration leads to macrophage differentiation [Moderate]

The monocyte subpopulations, CC chemokine receptor 2 (CCR2)highLy6C+ inflammatory monocytes and CCRlowLy6C resident monocytes, are generally thought to preferentially differentiate into M1 inflammatory macrophages and M2 anti-inflammatory macrophages, respectively, in early inflammation [16]. Ly6C monocytes dominate the early phase of myocardial infarction and exhibit phagocytic, proteolytic, and inflammatory functions, as well as digesting damaged tissues. However, Ly6C monocytes, recruited at a later phase of inflammation, have attenuated inflammatory properties and differentiate toward M2 macrophages and contribute to angiogenesis, genesis of myofibroblasts, and collagen deposition [17].

Oxidative stress leads to LDL oxidation [Moderate]

Under oxidative stress, the oxidation of LDL occurs by lipid peroxidation, primarily involving phospholipid molecules. Under pathological conditions, apolipoprotein B-containing lipoproteins in the plasma penetrate through the damaged endothelium into the vascular subendothelial intima where they are oxidized by ROS [18, 19].

Macrophage differentiation leads to foam cell formation [Moderate]

Monocytes migrate into the intima guided by chemokines [20] and differentiate into macrophages. These macrophages then take up modified lipoproteins and form foam cells as they accumulate excess lipids [21].

LDL oxidation leads to foam cell formation [Moderate]

Oxidized LDL (ox-LDL) is the archetypal source of cholesterol and inducer of foam cell formation [22]. The formation of fatty streaks is a major characteristic of atherosclerosis caused by the conversion of macrophages into foam cells. Foam cell formation is characterized by an accumulation of lipids, predominantly cholesterol esters [22, 23].

Foam cell formation leads to plaque formation [Moderate]

Subsequent cell apoptosis and necroptosis, complicated by failed efferocytosis (dead cell removal by phagocytes), lead to the formation of a lipid-rich necrotic core (NC) and production of thrombogenic tissue factors [24]. NC components and inflammatory cells promote the degradation of plaque-stabilizing extracellular fibrous matrix-like collagen and proteoglycans and thinning of the fibrous cap [25]. Hypoxia-inducible factors produced by cells contained in the NC promote pathologic neoangiogenesis, which favors intraplaque hemorrhage and further expansion of the NC. Unresolved inflammation triggers plaque calcification, which reduces further the mechanical stability of the plaque [25].

Plaque formation leads to plaque instability [Moderate]

After foam cell formation, the release of substances including matrix metalloproteinases (MMPs) increases monocyte mobilization and promotes the degradation of extracellular matrix proteins including collagen and fibronectin [26]. This process leads to plaque instability and eventually plaque rupture [27, 28].

Plaque instability leads to thrombosis [Moderate]

Mature atherosclerotic plaques are composed of a lipid core that is separated from the vessel lumen by a cap composed of fibrillar collagen [29]. Disruption of this cap exposes the plaque’s underlying thrombogenic core to the bloodstream, resulting in thromboembolism. This process of ‘plaque rupture’ is the main cause of acute coronary syndromes [30-33] and ischemic cerebral events [34-36].

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Biological plausibility and empirical support for KERs

Although ROS are generated under normal daily activity, they can be eliminated by homeostasis. Dysfunctional homeostasis and unhealthy daily habits can promote the persistent generation of ROS, resulting in chronic and high-level oxidative stress, which eventually leads to thrombosis. In general, the biological plausibility of causal linkage from reactive oxygen species as well as oxidative stress through various diseases including thrombosis is well established.

Support for the biological plausibility of KERs is summarized in the table below.


Support for biological plausibility of KERs

MIE => KE 1

ROS generally activates the anti-oxidant system to maintain homeostasis of cellular functions. An imbalance between ROS and the anti-oxidant system leads to cellular oxidative stress, whereby cellular components are oxidized to be malfunctional.

Biological plausibility of the MIE => KE1 is high.

There is a well-established mechanistic understanding between MIE-->KE1.

KE 1 => KE 2

Oxidative stress promotes an intracellular oxidative environment, which causes an uncoupling of endothelial nitric oxide synthase (eNOS). NO bioavailability is crucial to maintain vascular tone. Oxidative stress also alters the barrier integrity of endothelial cells and irregular expression of adhesion molecules such as ICAM-1.

Biological plausibility of KE1 => KE2 is high.

Oxidative stress is one cause of endothelial dysfunction. Inflammatory responses are also involved in endothelial dysfunction. However, a direct relationship between KE1 and KE2 is consistent with current biological knowledge.

KE 1 => KE 5

Oxidative stress leads to the generation of excess ROS, which causes the lipid peroxidation of LDL as well as apoB modification. The final product is oxidized LDL.

Biological plausibility of KE1 => KE5 is high.

Strong relationship between KE1 => KE5 is well-established and consistent with current biological knowledge.

KE 2 => KE 3

Endothelial dysfunction enables the easy access of circulating immune cells to the vascular intima, accompanied by the upregulation of adhesion molecules and disruption of the barrier integrity. Circulating monocytes attached to dysfunctional endothelial cells via adhesion molecules then penetrate into the intima.

Biological plausibility of KE2 => KE3 is high.

The functional relationship between KE 2 and KE 3 is consistent with current biological knowledge.

KE 3 => KE 4

Infiltrated monocytes are differentiated into macrophages by autocrine and paracrine mechanisms. Dysfunctional endothelial cells allow various immune cells to penetrate into the intima region. Oxidative stress also contributes to the activation of these immune cells, leading to the secretion of inflammatory cytokines, which promote the differentiation of monocytes into macrophages

Biological plausibility of KE3 => KE4 is high.

KE 4 and KE 5=> KE 6

Activated macrophages express receptors for LDL uptake. Representative receptors are the scavenger receptor and LOX-1. Macrophages uptake lipoproteins, especially oxidized-LDL, which accumulates inside the cells, termed foam cells.

Biological plausibility of KE4 => KE5 is high.

KE6 =>KE7

Accumulated foam cells then die via necrosis. Cell debris and lipids released from the necrotic foam cells form plaques. During plaque formation, smooth muscle cells migrate underneath endothelial cells and express extracellular matrix to form a fibrous cap.

Biological plausibility of KE5 => AO is high.

KE7 =>KE8

Cell death of the migrated smooth muscle cells causes a thinning of the fibrous cap. Extracellular matrix in the fibrous cap is also degraded by proteinases including matrix metalloproteinases. An unstable fibrous cap causes vulnerable plaques.

Biological plausibility of KE6 => AO is high.

KE8 =>KE9

Vulnerable plaques finally rupture and components in the plaques are eroded. Platelets accumulate and form a thrombus.

Biological plausibility of KE7 => AO is high.

Empirical Support for KERs

MIE => KE 1

Oxidative stress is a condition whereby excess intracellular ROS is not scavenged. The source of ROS varies, for example, chemical substances induce ROS via biological processes including metabolism and mitochondrial activity. ROS inhibitors such as N-acetylcysteine attenuate oxidative stress.

Empirical support of the KER between MIE and KE1 is high.

KE 1 => KE 2

Treatment with the causative substances of ROS induction as well as oxidative stress, including hydrogen peroxide, causes endothelial dysfunction. For example, the increased expression of adhesion molecules and monocyte-endothelial adhesion are observed.

These phenomena are caused by oxidative stress-induced inflammatory responses, and the scavenging of exogenous ROS with inhibitors such as N-acetylcysteine ameliorates oxidative stress-inducible endothelial dysfunction.

Empirical support of the KER between KE1 and KE2 is high.

KE 1 => KE 5

Circulating native LDL infiltrates into the intima region of the vasculature, where ROS oxidizes LDL to form oxidized-LDL (Ox-LDL). ROS inhibitors (e.g., NAC, resveratrol, ascorbate) attenuate the oxidative modification of LDL.

Empirical support of the KER between KE1 and KE5 is high.

KE 2 => KE 3

Monocyte infiltration is initiated by monocyte-endothelial adhesion via adhesion molecules expressed on the apical surface of endothelial cells. Adherent monocytes then infiltrate into the intima region of the vasculature. Increased expression of adhesion molecules and a leaky endothelial barrier are representative features of endothelial dysfunction. ICAM-1 deficiency in ApoE KO mice resulted in fewer atherosclerotic lesions, possibly because of the reduced recruitment of monocytes into the intima. However, few studies have provided direct evidence for a relationship between endothelial dysfunction and monocyte infiltration.

Empirical support of the KER between KE2 and KE3 is low.

KE 3 => KE 4

Monocytes differentiate into macrophages. Many studies reported that various stimuli such as proinflammatory cytokines promote this differentiation. Atherogenic vasculature produces proinflammatory cytokines; thus, theoretically, the infiltrated monocytes should be differentiated into macrophages in the intima. An increase in macrophage-like cells is observed in atherosclerotic lesions; however, direct evidence demonstrating infiltrated monocyte differentiation is limited.

Empirical support of the KER between KE3 and KE4 is moderate.

KE 4 and KE 5=> KE 6

Cumulative evidence suggests macrophages change their appearance related to the intracellular accumulation of lipids, leading to the formation of foam cells. The uptake of lipids, especially ox-LDL, is crucial for atherosclerotic lesions and is promoted by its receptors LOX-1 and scavenger receptor (CD36). A deficiency in these receptors results in reduced areas of lipid staining in arteries.

Empirical support of the KER between KE4-KE5 and KE6 is moderate.

KE6 =>KE7

Inhibition of foam cell formation via the attenuation of scavenger receptors resulted in atherosclerotic plaque formation in ApoE KO mice.

Empirical support of the KER between KE6 and KE7 is moderate.

KE7 =>KE8

Plaque instability is caused by several metalloproteinases, and their inhibition was reported to prevent vulnerable atherosclerotic plaques [1].

Empirical support of the KER between KE7 and KE8 is moderate.

KE8 =>AO

Various blood components aggregate at the site of endothelial rupture. Tissue factors induced by inflammation and eroded by endothelial rupture have a critical role in this region, and their inhibition effectively reduced thrombosis [37].

Empirical support of the KER between KE8 and AO is moderate.

Concordance of dose-response relationships

Studies presenting a clear dose-response relationship in the late stages of this AOP are limited because the later KEs are caused by the cumulative or constitutive effects of the earlier stages. Much evidence of dose-response relationships in the earlier KEs was reported; however, data of the later stages are sparse. In brief, oxidative stress (MIE) is caused by an imbalance between oxidants and their scavenging by anti-oxidant systems such as glutathione. The disruption of an anti-oxidant system was reported to be dose-dependent. Similarly, endothelial dysfunction was also dose-dependent; oxidative and proinflammatory chemical substances lead to eNOS instability, impaired barrier integrity, and increased adhesion molecule expression. However, the acute incidence of the early phase KEs including endothelial dysfunction is normally cleared by the homeostatic capacity of the vasculature; therefore, elicitation of the later KEs needs the consecutive or frequent occurrence of the earlier KEs rather than the strength of stimuli. Monocyte infiltration (KE3) requires the expression of adhesion molecules on the apical surface of endothelial cells, but at the appropriate time. Although macrophage differentiation (KE4) is promoted by proinflammatory cytokines, this occurs in a consecutive manner, not by a single stimulus. In this sense, consecutive inflammation in the vasculature is necessary for the differentiation of infiltrated monocytes into macrophages. LDL oxidation appears to be dose-dependent because the level of oxidants determines the fate of LDL. However, LDL is generally oxidized in the intima region of the vasculature; therefore, the causative oxidants are probably generated in the intima under oxidative conditions. KE7 through AO is a biological event that is cumulative of the earlier Kes; therefore, a dose-response relationship between apical exposure to chemicals and biological events is not obvious. Nevertheless, strong stimulation of the vascular system requires a long time to clear the early key events; thus, consecutive unhealthy conditions in the vasculature are likely to occur in a dose-dependent manner.

Temporal concordance among the key events and adverse effects

Few studies have evaluated the temporal concordance throughout this AOP. However, key event relationships between the KEs acutely elicited by stressors are well studied and established. Endothelial dysfunction (KE1) is strongly associated with oxidative stress, because excess ROS is generated in cells under oxidative stress conditions, and ROS decreased nitric oxide, inflammation, and apoptosis in the vasculature, which eventually impair endothelial functions. Temporal concordance of the relationship between MIE and KE1 has been elucidated by time-course analyses and ROS scavenging. Temporal concordance among other key events is empirically or theoretically understood; however, robust evidence for most KERs is lacking from the viewpoint of time-course analyses or inhibition of specific KEs.

Uncertainties, inconsistencies, and data gaps

Uncertainties underlying this AOP include individual variability in the anti-oxidant capacity. As mentioned previously, oxidative stress is a condition whereby excess ROS is generated intracellularly, leading to the oxidation of intracellular components. Intracellular ROS levels are generally determined by the balance between ROS and the anti-oxidant capacity of cells. However, the anti-oxidant capacity varies between individuals related to their age, dietary behavior, smoking habits, and exercise.

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help
Modulating Factor (MF) Influence or Outcome KER(s) involved

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

ROS induction is well-understood in terms of the dose-response relationship and various studies elucidated the quantitative relationship between intracellular ROS levels, endothelial dysfunction, and stressors [38]. However, this AOP is based upon chronic exposure to stressors, and not a single exposure. In addition, the level of stressors should be varied over time. Therefore, the progress of the AOP is influenced by environmental conditions and individual homeostatic capacity. Because there are many confounding factors for this AOP, a quantitative understanding of KERs is needed to determine how chronic elevation of intracellular ROS levels induced by a stressor could influence the downstream KEs and AO.

Currently, there is a good quantitative understanding of how ROS activation influences oxidative stress, endothelial dysfunction, monocyte infiltration, macrophage differentiation, LDL oxidation, and foam cell formation. In addition, in most of the previous studies, the summary evidence indicates dose-response relationships, time-response relationships, and causality for ROS activation leading to increased oxidative stress, lending strong support for these KERs. However, quantitative knowledge is lacking with respect to the identity of thrombosis undergoing plaque formation and plaque instability, which makes empirical support for these KERs weak. Furthermore, data on plaque formation and plaque instability at the biological level were mainly obtained from surrogate measures, which are accepted in clinical practice as indicators of thrombosis, although they may not adequately reflect quantitative values. Taken together, quantitative evidence for the KERs at the tissue and organism levels is moderate at best.

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help


List of the literature that was cited for this AOP. More help
  1. Li, T., et al., The Role of Matrix Metalloproteinase-9 in Atherosclerotic Plaque Instability. Mediators Inflamm, 2020. 2020: p. 3872367.
  2. Benjamin, E.J., et al., Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association. Circulation, 2019. 139(10): p. e56-e528.
  3. Curtis, A.B., et al., Arrhythmias in Patients >/=80 Years of Age: Pathophysiology, Management, and Outcomes. J Am Coll Cardiol, 2018. 71(18): p. 2041-2057.
  4. North, B.J. and D.A. Sinclair, The intersection between aging and cardiovascular disease. Circ Res, 2012. 110(8): p. 1097-108.
  5. Iorga, A., et al., The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy. Biol Sex Differ, 2017. 8(1): p. 33.
  6. Villa, A., et al., Estrogen accelerates the resolution of inflammation in macrophagic cells. Sci Rep, 2015. 5: p. 15224.
  7. Xue, B., et al., Protective actions of estrogen on angiotensin II-induced hypertension: role of central nitric oxide. Am J Physiol Heart Circ Physiol, 2009. 297(5): p. H1638-46.
  8. Phaniendra, A., D.B. Jestadi, and L. Periyasamy, Free radicals: properties, sources, targets, and their implication in various diseases. Indian J Clin Biochem, 2015. 30(1): p. 11-26.
  9. Singh, U. and I. Jialal, Oxidative stress and atherosclerosis. Pathophysiology, 2006. 13(3): p. 129-42.
  10. Konior, A., et al., NADPH oxidases in vascular pathology. Antioxid Redox Signal, 2014. 20(17): p. 2794-814.
  11. Shimada, K., et al., N-acetylcysteine reduces the severity of atherosclerosis in apolipoprotein E-deficient mice by reducing superoxide production. Circ J, 2009. 73(7): p. 1337-41.
  12. Habas, K. and L. Shang, Alterations in intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in human endothelial cells. Tissue Cell, 2018. 54: p. 139-143.
  13. Roebuck, K.A., Oxidant stress regulation of IL-8 and ICAM-1 gene expression: differential activation and binding of the transcription factors AP-1 and NF-kappaB (Review). Int J Mol Med, 1999. 4(3): p. 223-30.
  14. van Haperen, R., et al., Reduction of blood pressure, plasma cholesterol, and atherosclerosis by elevated endothelial nitric oxide. J Biol Chem, 2002. 277(50): p. 48803-7.
  15. Kitagawa, K., et al., Involvement of ICAM-1 in the progression of atherosclerosis in APOE-knockout mice. Atherosclerosis, 2002. 160(2): p. 305-10.
  16. Auffray, C., et al., Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science, 2007. 317(5838): p. 666-70.
  17. Yang, J., et al., Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases. Biomark Res, 2014. 2(1): p. 1.
  18. Kruth, H.S., et al., Macrophage foam cell formation with native low density lipoprotein. J Biol Chem, 2002. 277(37): p. 34573-80.
  19. Harrison, D., et al., Role of oxidative stress in atherosclerosis. Am J Cardiol, 2003. 91(3a): p. 7a-11a.
  20. Hansson, G.K., Inflammatory mechanisms in atherosclerosis. J Thromb Haemost, 2009. 7 Suppl 1: p. 328-31.
  21. Tsimikas, S. and Y.I. Miller, Oxidative modification of lipoproteins: mechanisms, role in inflammation and potential clinical applications in cardiovascular disease. Curr Pharm Des, 2011. 17(1): p. 27-37.
  22. Woollard, K.J. and F. Geissmann, Monocytes in atherosclerosis: subsets and functions. Nat Rev Cardiol, 2010. 7(2): p. 77-86.
  23. Kruth, H.S., Receptor-independent fluid-phase pinocytosis mechanisms for induction of foam cell formation with native low-density lipoprotein particles. Curr Opin Lipidol, 2011. 22(5): p. 386-93.
  24. Stefanadis, C., et al., Coronary Atherosclerotic Vulnerable Plaque: Current Perspectives. J Am Heart Assoc, 2017. 6(3).
  25. Bentzon, J.F., et al., Mechanisms of plaque formation and rupture. Circ Res, 2014. 114(12): p. 1852-66.
  26. Wang, X. and R.A. Khalil, Matrix Metalloproteinases, Vascular Remodeling, and Vascular Disease. Adv Pharmacol, 2018. 81: p. 241-330.
  27. Newby, A.C., et al., Vulnerable atherosclerotic plaque metalloproteinases and foam cell phenotypes. Thromb Haemost, 2009. 101(6): p. 1006-11.
  28. Thomas, A.C., et al., Foam Cell Formation In Vivo Converts Macrophages to a Pro-Fibrotic Phenotype. PLoS One, 2015. 10(7): p. e0128163.
  29. in Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists, R. Fitridge and M. Thompson, Editors. 2011, University of Adelaide Press
  30. Falk, E., P.K. Shah, and V. Fuster, Coronary plaque disruption. Circulation, 1995. 92(3): p. 657-71.
  31. Falk, E., Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation, 1985. 71(4): p. 699-708.
  32. Libby, P., Current concepts of the pathogenesis of the acute coronary syndromes. Circulation, 2001. 104(3): p. 365-72.
  33. Shah, P.K., Plaque disruption and thrombosis: potential role of inflammation and infection. Cardiol Rev, 2000. 8(1): p. 31-9.
  34. Carr, S., et al., Atherosclerotic plaque rupture in symptomatic carotid artery stenosis. J Vasc Surg, 1996. 23(5): p. 755-65; discussion 765-6.
  35. Loftus, I.M., et al., Increased matrix metalloproteinase-9 activity in unstable carotid plaques. A potential role in acute plaque disruption. Stroke, 2000. 31(1): p. 40-7.
  36. Sitzer, M., et al., Plaque ulceration and lumen thrombus are the main sources of cerebral microemboli in high-grade internal carotid artery stenosis. Stroke, 1995. 26(7): p. 1231-3.
  37. Badimon, L., T. Padro, and G. Vilahur, Atherosclerosis, platelets and thrombosis in acute ischaemic heart disease. Eur Heart J Acute Cardiovasc Care, 2012. 1(1): p. 60-74.
  38. Park, W.H., The effects of exogenous H2O2 on cell death, reactive oxygen species and glutathione levels in calf pulmonary artery and human umbilical vein endothelial cells. Int J Mol Med, 2013. 31(2): p. 471-6.