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R E V I E W Open Access
The critical role of endothelial function in
fine particulate matter-induced
atherosclerosis
Shuang Liang
1,2
, Jingyi Zhang
1,2
, Ruihong Ning
1,2
, Zhou Du
1,2
, Jiangyan Liu
1,2
, Joe Werelagi Batibawa
1,2
,
Junchao Duan
1,2*
and Zhiwei Sun
1,2*
Abstract
Ambient and indoor air pollution contributes annually to approximately seven million premature deaths. Air
pollution is a complex mixture of gaseous and particulate materials. In particular, fine particulate matter (PM
2.5
)
plays a major mortality risk factor particularly on cardiovascular diseases through mechanisms of atherosclerosis,
thrombosis and inflammation. A review on the PM
2.5
-induced atherosclerosis is needed to better understand the
involved mechanisms. In this review, we summarized epidemiology and animal studies of PM
2.5
-induced atherosclerosis.
Vascular endothelial injury is a critical early predictor of atherosclerosis. The evidence of mechanisms of PM
2.5
-induced
atherosclerosis supports effects on vascular function. Thus, we summarized the main mechanisms of PM
2.5
-triggered
vascular endothelial injury, which mainly involved three aspects, including vascular endothelial permeability, vasomotor
function and vascular reparative capacity. Then we reviewed the relationship between PM
2.5
-induced endothelial injury
and atherosclerosis. PM
2.5
-induced endothelial injury associated with inflammation, pro-coagulation and lipid deposition.
Although the evidence of PM
2.5
-induced atherosclerosis is undergoing continual refinement, the mechanisms of PM
2.5
-
triggered atherosclerosis are still limited, especially indoor PM
2.5
. Subsequent efforts of researchers are needed to improve
the understanding of PM
2.5
and atherosclerosis. Preventing or avoiding PM
2.5
-induced endothelial damage may greatly
reduce the occurrence and development of atherosclerosis.
Keywords: PM
2.5
, Endothelial dysfunction, Inflammation, Coagulation, Lipid deposition, Atherosclerosis
Background
The World Health Organization (WHO) reported that
approximately 91% of people worldwide live in un-
healthy environments where air quality levels exceed
WHO limits. The combined effects of indoor and ambient
air pollution result in approximately 7 million premature
deaths from noncommunicable diseases every year [1].
Chemicals in the air initiate or potentiate a wide range of
noncommunicable diseases [2]. Fine particulate matter
(PM
2.5
, the aerodynamic diameter ≤2.5 μm) in air pollution
became the fifth death risk factor in 2015 [3]. PM
2.5
is a
complex mixture, and its major source is combustion, such
as traffic-related diesel exhaust particles (DEPs), industry,
indoor cooking activities, and bushfires [4]. For example,
the Australian bushfires in 2019-2020 had extreme impacts
on air quality throughout the region and even the globally
[5]. Thus, the global burden of cardiovascular disease
caused by PM
2.5
may be much greater than that previously
reported by WHO. Evidence has indicated that PM
2.5
in-
duces lipid metabolism dysregulation and increases hyper-
tension and the prevalence of cardiac arrhythmias, thus
accelerating the progression of atherosclerosis, and increas-
ing the risk of cardiovascular disease- and stroke-related
mortality [6–9].
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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the
data made available in this article, unless otherwise stated in a credit line to the data.
* Correspondence: jcduan@ccmu.edu.cn;zwsun@hotmail.com
1
Department of Toxicology and Sanitary Chemistry, School of Public Health,
Capital Medical University, Beijing 100069, People’s Republic of China
Full list of author information is available at the end of the article
Liang et al. Particle and Fibre Toxicology (2020) 17:61
https://doi.org/10.1186/s12989-020-00391-x
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Atherosclerosis is a chronic inflammatory disease of
large and medium-sized arteries. The causes of athero-
sclerosis are inflammation, hemodynamic damage and
abnormal lipid metabolism in early-stage atherosclerosis
[10]. When endothelial cells are activated, they express
inflammatory cytokines (such as interleukin (IL)-8,
monocyte chemoattractant protein (MCP)-1) and adhe-
sion molecules (such as intercellular adhesion molecule
(ICAM-1) and vascular cell adhesion molecule (VCAM-
1)), attracting blood monocytes that bind to the acti-
vated endothelial monolayer and infiltrate the arterial
wall. Important biomarkers of the development of ath-
erosclerotic inflammation include C-reactive protein
(CRP), IL-6, adhesion molecules, and matrix metallopro-
teinases (MMPs) [10]. These factors induce macrophage
polarization into the pro-inflammatory M1-like or anti-
inflammatory M2-like phenotype [11]. The scavenger re-
ceptors of macrophages, such as low-density lipoprotein
receptor-related protein 1 (LRP1), cluster of differenti-
ation 36 (CD36) and class B type 1 (SR-B1), play a key
role in lipid uptake, deposition and the development of
atherosclerotic plaques [12–14]. Liver X receptor α
(LXR-α)/ATP-binding cassette transporter A1 (ABCA1)/
ABCG1-dependent cholesterol efflux is a crucial event in
the suppression of lipid accumulation during the trans-
formation of macrophage foam cells [15]. Vascular
smooth muscle cells (VSMCs) migrate from the media
to the intima, synthesize extracellular matrix macromol-
ecules such as elastin, proteoglycans and collagen, and
form fibrous caps formation. The death of foam cells
and VSMCs leads to the release of extracellular lipids in
atherosclerotic lesions, leading to the formation of a nec-
rotic core [11,16]. MMPs (such as MMP-9) are highly
expressed in atherosclerotic plaques, leading to substan-
tial enhancement of elastin degradation and inducing
plaque rupture [17]. Currently, several imaging tech-
niques can be used to investigate plaques and signs of
vulnerability, such as CT, magnetic resonance imaging
(MRI) and ultrasound [18]. Molecular imaging is an
innovative technique for the detection of plaque in-
flammation. The utility of several nanoparticles, such
as sodium fluoride, iron oxide and polyethylene glycol
molecules, for the molecular imaging of atheroscler-
osis in animal models and patients has been investi-
gated [19–21]. In the past few decades, treatment
strategies for atherosclerosis have mainly focused on
lowering lipid levels with high-intensity statins. How-
ever, only approximately 25% of patients who receive
high-intensity statins as a lipid-lowering therapy
achieve the recommended level of low-density lipo-
protein cholesterol (LDL-C, ≤1.8 mmol/L) [22]. Ap-
proximately 75% of patients do not respond to statin
therapy sufficiently; therefore, novel therapeutic strat-
egies are needed.
PM
2.5
is a complex mixture, and a review had compre-
hensively summarized the chemical composition and
characteristics of PM
2.5
, including inorganic elements,
water-soluble ions, carbonaceous aerosols and organic
compounds (polycyclic aromatic hydrocarbons (PAHs)
and volatile organic compounds (VOCs) etc) [4].. A
study showed that coal combustion and vehicular emis-
sions are the main sources of PAHs and VOCs in PM
2.5
[23,24]. Evidence has demonstrated that DEPs acceler-
ate the development or exacerbation of atherosclerosis
[25,26]. Organic chemicals from DEPs, such as PAHs
adhere to the carbon cores of particles, and certain
PAHs can trigger Ca
2+
signaling and increase inflamma-
tion in endothelial cells [27–30]. Evidence has shown
that the levels of urinary PAH biomarkers are associated
with cardiovascular disease [31]. Due to the antagonistic
and synergic effects of complex VOC mixtures, the toxic
effects of VOCs are difficult to estimate [32]. In addition,
the surface of particles may bind reactive copollutants,
including biomolecules (such as endotoxins), redox-
active transition metals, and reactive quinones/alde-
hydes, which may be carried by particles and enter lung
tissue and the circulation, inducing secondary toxicity
[33,34]. The ions and metal components of PM
2.5
, in-
cluding SO
42−
,K
+
,Cl
−
, K, Si, As, Zn, Se and Pb, could
be mainly responsible for systemic inflammation [35].
Evidence has shown that the binding of endotoxins to
the surface of PM
2.5
particles plays a critical role in the
inflammatory response. Endotoxin neutralizer (poly-
myxin B) and knockout of toll-like receptor 4 (TLR4)
strongly inhibit the PM
2.5
-triggered inflammatory re-
sponse [36]. However, the understanding of the major
toxic effects exerted by the specific components of PM
2.5
is limited. Further investigating the toxicity of PM
2.5
components will contribute to a comprehensive under-
standing of PM
2.5
, which may be a key area of future
research.
Endothelial cells cover the internal surface of blood
vessels, and the integral endothelial cell layer maintains
a complex functional balance to inhibit the inflammatory
response or thrombosis. Ambient PM
2.5
exposure elicits
the deterioration of endothelial function, systemic in-
flammation and coagulation [37,38]. Evidence has
shown that a 10 μg/m
3
increase in the PM
2.5
concentra-
tion at a 1-day lag was associated with increased
brachial-ankle pulse wave velocity (baPWV, a physio-
logical indicator of arterial stiffness), but not with high-
sensitivity C-reactive protein (hsCRP, a biomarker of
vascular inflammation) levels; thus, arterial stiffness
might be more sensitive to ambient PM
2.5
exposure than
inflammation [39]. Accordingly, indoor PM
2.5
also in-
duces endothelial dysfunction and inhibits blood vessel
formation but has no significant association with arterial
stiffness [40,41]. Endothelial dysfunction disrupts anti-
Liang et al. Particle and Fibre Toxicology (2020) 17:61 Page 2 of 24
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inflammatory processes, anti-platelet aggregation, anti-
thrombotic processes and vascular repair in vivo [42].
Alterations in vascular function might be the earliest
pathophysiological mechanism contributing to air
pollution-mediated cardiovascular diseases, and indeed,
such changes are a critical early predictor of atheroscler-
osis [43,44]. However, there is a lack of systematic un-
derstanding of the mechanism of PM
2.5
-induced
endothelial dysfunction. Moreover, a review focused on
scientific evidence that DEPs induce endothelial dysfunc-
tion, including bioavailability and mechanisms, and is re-
lated to cardiovascular injury [45].
Therefore, this review mainly provides an overview of
the literature related to PM
2.5
and atherosclerosis, and
discusses the mechanism of PM
2.5
-induced vascular
endothelial injury. Approximately 30% of ambient PM
2.5
is attributable to traffic sources [46–48]. Thus, we also
review evidence for the role DEPs in atherosclerosis and
endothelial dysfunction in this review. Fig. 1summarizes
the main mechanisms of PM
2.5
-triggered atherosclerosis.
We review the main mechanisms of endothelial dysfunc-
tion after exposure to ambient or indoor PM
2.5
. Further-
more, we discuss the role of ambient PM
2.5
-induced
vascular endothelial injury in the development of athero-
sclerosis. Targeting endothelial injury, as the initial
pathological process of atherosclerosis, is the key to pre-
venting the occurrence of atherosclerotic cardiovascular
disease. Therefore, a scientific understanding of the
mechanism of PM
2.5
-induced endothelial dysfunction
will play a critical role in the prevention and treatment
of atherosclerosis and other cardiovascular-related
diseases.
PM
2.5
and atherosclerosis
As shown in Fig. 1, four main hypotheses by which in-
haled particulate matter affects the cardiovascular sys-
tem have been proposed: a. Inhaled particulate matter
reaches the terminal bronchioles and enters alveoli,
inducing an inflammatory response in the lung; b. Re-
leased inflammatory mediators and unidentified media-
tors enter the circulation; c. A small proportion of
particles reach the circulation; and d. Inhaled particulate
matter activates alveoli sensory receptors, leading to
autonomic imbalance [49]. Fig. 1summarizes the main
mechanisms of PM
2.5
-triggered atherosclerosis. Endothe-
lial injury increases the release of IL-6, VCAM-1, ICAM-
1, and other inflammatory cytokines, recruiting blood
monocytes that bind to the activated endothelial mono-
layer. The bound monocytes migrated directly into the
intima and mature into macrophages. PM
2.5
increases
the expression of CD36 in plaque macrophages and me-
diates the abnormal accumulation of oxidized lipids
(such as 7-ketocholesterol, 7-KCh), finally promoting
foam cell formation [12]. TLR4 recognizes modified
lipoprotein, which mediates lipoprotein accumulation in
macrophages [50]. Jin Geng et al. showed that PM
2.5
can
trigger foam cell formation via the TLR4/MyD88/NF-κB
pathway [51]. Oxidized low-density lipoprotein (ox-LDL)
primes and activates the NOD-like receptor protein 3
(NLRP3) inflammasome by binding to TLR4 or CD36 in
macrophages and increases the release of inflammatory
cytokines (IL-1βand IL-18) and pyroptosis [11]. PM
2.5
induces oxidative stress, increasing the apoptosis of foam
cells via the mitochondrial apoptosis pathway [52].
PM
2.5
impairs HDL functions such as HDL-mediated
cholesterol efflux, thus facilitating foam cell formation
and accumulation [53]. Apoptotic cells are not quickly
and efficiently engulfed and decomposed by phagocytes,
resulting in secondary necrosis and the release of a large
amount of pro-inflammatory cytokines and thus contrib-
uting to the development of the necrotic core [54]. How-
ever, currently, there is a lack of evidence concerning
the efferocytosis of phagocytes in atherosclerosis in-
duced by PM
2.5
. In addition, oxidative stress induced by
PM
2.5
can increase the proliferation and foam cell for-
mation in VSMCs; however, future research is required
to demonstrate the role of oxidative stress in mediating
PM-triggered foam cell formation [55,56]. VSMCs
migrate from the media to the intima and synthesize
extracellular matrix macromolecules such as elastin, pro-
teoglycans and collagen, and fibrous cap formation.
However, reports concerning the migration of VSMCs
triggered by PM
2.5
are lacking. The death of foam cells
and the release of extracellular lipids in atherosclerotic
lesions lead to the formation of a necrotic core [11,16].
Table 1summarizes epidemiological studies on the as-
sociation between PM
2.5
exposure and atherosclerosis.
One of the major sources of ambient PM
2.5
is traffic-
derived emissions. Traffic noise is an important con-
founding factor in the effects of air pollutant exposure
from traffic, and evidence has demonstrated that night-
time traffic noise and PM
2.5
are both associated with a
3.9% (95% CI: 0.0 - 8.0%) increase in thoracic aortic cal-
cification (TAC)-burden per 5 dB(A) night-time traffic
noise and an 18.1% (95% CI: 6.6 - 30.9%) increase in
TAC burden per 2.4 μg/m
3
PM
2.5
. Importantly, both are
independently associated with the development and pro-
gression of subclinical atherosclerosis [59,71]. Carotid
intima-media thickness (CIMT) is defined as the dis-
tance between the lumen-intima and media-adventitia
borders of the common carotid artery and can be mea-
sured by vascular ultrasound; an increase in the CIMT is
a marker of subclinical atherosclerosis [93]. PM
2.5
expos-
ure is associated with an increase in the CIMT; more-
over, increased or slowed CIMT progression is
associated with PM
2.5
concentration [68]. The PM
2.5
components sulfur, elemental carbon (EC) and organic
carbon (OC), but not silicon, are associated with
Liang et al. Particle and Fibre Toxicology (2020) 17:61 Page 3 of 24
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increased CIMT, and OC has the strongest association
[69,78]. Long-term exposure to PM
2.5
can increase sys-
tematic inflammation, the levels of fibrofatty and nec-
rotic core components, and total plaque volume [38,79].
Short-term exposure to PM
2.5
is associated with inflam-
mation, coagulation, endothelial activation and ox-LDL
levels [38,63]. Table 2summarizes animal studies of
PM
2.5
-induced atherosclerosis. PM
2.5
promotes the
Fig. 1 Summarized the main pathogenic mechanisms of PM
2.5
-triggered atherosclerosis. Four main hypotheses have proposed by which inhaled
particulate matter effect on cardiovascular system [49]: a. inflammatory mediators; b. unidentified mediators; c. autonomic imbalance; d. direct
particle translocation. PM
2.5
increased endothelial permeability, declined vascular tone and vascular reparative capacity, thus induced vascular
endothelial injury. The initial step of atherosclerosis is vascular endothelial dysfunction, and then activated endothelial cells promoted monocytes
recruited and maturation of monocytes into macrophages. Lipid accumulation and continued uptake by macrophages lead to foam cell
formation and then developed into atherosclerotic lesion
Liang et al. Particle and Fibre Toxicology (2020) 17:61 Page 4 of 24
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Table 1 Epidemiological studies on the association between PM
2.5
exposure and atherosclerosis
Reference Location Study design Sample size Pollutants PM
2.5
Exposure Evaluation index Findings or association
[57] - Meta-analysis 9183 Ambient PM
2.5
,PM
10
,
PM
2.5abs
, PMcoarse,
NOx, NO
2
- CIMT PM
2.5
(per 5 μg/m
3
increase):
CIMT increased by 0.78% (95% CI:
-0.18%, 1.75%, p = 0.11).
[58] Ohio, United States Prospective
longitudinal
cohort
6575 Ambient PM
2.5
,NO
2
Long-term exposure Angiography PM
2.5
(per 2.2 μg/m
3
increase):
Mild coronary atherosclerosis
(defined as 1 to 2 vessels with ≥
50% stenosis) OR = 1.43 (95% CI:
1.11-1.83; p = 0.005); Severe
coronary atherosclerosis (defined
as 3 vessels with ≥50% stenosis)
OR = 1.63 (95% CI: 1.26 to 2.11; p
< 0.001).
[59] CA, USA Cross-sectional 4238 PM
2.5
, traffic noise Long-term exposure TAC PM
2.5
(per 2.4 μg/m
3
increase):
TAC burden increased by 18.1%
(95% CI: 6.6 to 30.9%).
[60] USA Longitudinal
cohort
6814 Ambient PM
2.5
NOx,
NO
2
and black carbon
Long-term exposure CAC; IMT PM
2.5
(per 5 μg/m
3
increase):
Coronary calcium progressed by
4.1 Agatson units per year (95% CI:
1.4 to 6.8);
Without association with IMT, -0.9
μm per year (95% CI: -3.0 to 1.3).
[61] India prospective,
intergenerational
cohort
3278 Ambient and indoor air
pollution
Long-term exposure CIMT Ambient PM
2.5
(per 1 μg/m
3
increase):
CIMT increased by 1.79% (95% CI:
-0.31 to 3.90) in all participants;
CIMT increased by 2.98% (95% CI:
0.23 to 5.72) in men.
Indoor air pollution (biomass
cooking fuel):
CIMT increased by 1.60% (95% CI:
-0.46 to 3.65) in all participants
[62] - Meta-analysis - PM
2.5
- CIMT
arterial calcification;
ankle-brachial index
PM
2.5
(per 10 μg/m
3
increase):
CIMT increased by 22.52 μm(p=
0.06); Without association with
arterial calcification (p = 0.44) or
ankle-brachial index (p = 0.85).
[63] USA Cross-sectional 6654 Ambient PM
2.5
and
black carbon
12 months,
3 months
2 weeks
Short-term exposure
(0-5 days)
HDL-C
HDL particle number
No significant association between
PM
2.5
and HDL-C;
PM
2.5
(per 5 μg/m
3
increase)
exposure for 3 months:
HDL-P decreased by 0.64 μmol/L
(95% CI: -1.01 to -0.26);
PM
2.5
(per 5 μg/m
3
increase)
exposure for 2-week:
HDL-C increased by -0.86 mg/dL
(95% CI: -1.38 to -0.34); HDL-P de-
creased by 0.29 μmol/L (95% CI:
-0.57 to -0.01).
PM
2.5
(per 5 μg/m
3
increase)
exposure for 5 days:
HDL-P decreased by 0.21 μmol/L
(95% CI: -0.38 to -0.04).
Liang et al. Particle and Fibre Toxicology (2020) 17:61 Page 5 of 24
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Table 1 Epidemiological studies on the association between PM
2.5
exposure and atherosclerosis (Continued)
Reference Location Study design Sample size Pollutants PM
2.5
Exposure Evaluation index Findings or association
[64] Beijing, China Panel study 40 Ambient PM
2.5
Short-term exposure
(1 day)
Ox-LDL; sCD36 PM
2.5
chloride, strontium, iron (1-
day, per 0.51 μg/m
3
increase) and
nickel (2-day, 2.5 μg/m
3
increase):
ox-LDL increased by 1.9% (95% CI:
0.2% to 3.7%, p < 0.05) and 1.8%
(95% CI: 0.2% to 3.4%), respectively;
PM
2.5
calcium (1-day, 0.7 μg/m
3
increase):
sCD36 increased by 4.8% (95% CI:
0.7% to 9.1%).
[65] Beijing, China Cross-sectional 8867 Ambient PM
2.5
,NO
2
,O
3
Long-term exposure CAC Score PM
2.5
(per 30 μg/m
3
increase):
CAC scores increased by 27.2%
(95% CI: 10.8% to 46.1%); CAC
increased by 42.2% (95% CI: 24.3%
to 62.7%) in men, 50.1% (95% CI:
28.8% to 75%) in elderly
participants, 62.2% (95% CI: -1.4%
to 20.4%) in those with diabetes.
[66] Taiwan Cross-Sectional 689 Ambient PM
10
,PM
2.5
,
PM
2.5
abs, NO
2
, NOx
Long-term exposure CIMT PM
2.5
abs (per 1.0 x 10
-5
/m):
Maximum left CIMT increased by
4.23% (95% CI: 0.32% to 8.13%, p <
0.05); PM
2.5
mass concentration
was not associated with CIMT.
[67] Toronto Cohort study 30 Urban PM
2.5
and O
3
Short-term exposure
(2 h)
HOI;
Blood pressure;
PM
2.5
(exposure for 2h, 1h after
exposure):
Association with HOI (p = 0.078);
HOI associated with systolic blood
pressure (p = 0.05).
[68] USA Cross-sectional,
longitudinal
5276 PM
2.5
Long-term exposure CIMT PM
2.5
concentration (per 2.5 μg/m
3
increase):
Increased IMT progression (5.0 μm/
y, 95% CI: 2.6 to 7.4 μm/y);
PM
2.5
concentration (per 1 μg/m
3
reduce):
Slowed IMT progression (-2.8 μm/y,
95%CI: -1.6 to -3.9μm/y).
[69] USA Cross-sectional 5488 Ambient PM
2.5
Long-term exposure CIMT PM
2.5
(sulfur, silicon, EC and OC):
Association: CIMT
Sulfur (0.022 mm, 95% CI: 0.014 to
0.031); silicon (0.006 mm, 95% CI:
0.000 to 0.012); OC (0.026 mm,
95% CI: 0.019 to 0.034).
[70] South India Cross-sectional 7000 PM
2.5
- CIMT PM
2.5
(per 1 μg/m
3
increase):
Association: CIMT.
[71] Germany Cohort study 4814 Traffic- related air
pollution and noise
Long-term exposure TAC No associations between PM
2.5
and TAC
[72] USA Longitudinal 165675 Ambient PM (PM
10
,
PM
2.5
,PM
2.5-10
)
Long-term exposure;
Short-term exposure
Leukocyte Counts and
Composition
PM
2.5
(per 10 μg/m
3
increase,
exposure for 1-month):
Increased: leukocyte count (12
cells/μl, 95%CI: -9 to 33),
granulocyte proportion (1.2%, 95%
CI: 0.6% to 1.8%);
Liang et al. Particle and Fibre Toxicology (2020) 17:61 Page 6 of 24
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Table 1 Epidemiological studies on the association between PM
2.5
exposure and atherosclerosis (Continued)
Reference Location Study design Sample size Pollutants PM
2.5
Exposure Evaluation index Findings or association
Decreased: CD8
+
T cell (-1.1%,
95%CI: -1.9% to -0.3%);
PM
2.5
(per 10 μg/m
3
increase,
exposure for 12-month):
Increased: leukocyte count (28
cells/μl, 95%CI: -20 to 75),
granulocyte proportion (1.1%, 95%
CI: -0.2% to 2.4%);
Decreased: CD8
+
T cell (-1.3%,
95%CI: -2.4% to -0.1%);
[38] USA Longitudinal 6814 Ambient PM
2.5
Long-term exposure;
Short-term exposure
Serum CRP, IL-6, fibrinogen,
D-dimer, soluble E-selectin,
sICAM -1
Long-term exposure to PM
2.5
( per
10 μg/m
3
increase):
Association: inflammation and
fibrinolysis (CRP, fibrinogen and E-
selectin);
Increased: e.g. IL-6 (6%, 95%CI: 2%
to 9%).
Short-term exposure to PM
2.5
:
Association: inflammation,
coagulation and endothelial
activation.
[73] Netherlands Prospective
cohort
750 Air pollutants (PM
2.5
,
NO
2
, black smoke, SO
2
)
Long-term exposure CIMT; PWV; AIx PM
2.5
(per 5 μg/m
3
increase):
CIMT increased by 0.94% (95% CI:
-.2.59% to 4.47%);
PWV increased by 0.64% (95% CI:
-4.71% to 6.01%);
AIx increased by 10.17% (95% CI:
-37.82% to 58.17%);
[74] USA Cohort study 3996 PM
2.5
,PM
10
Long-term exposure radial artery pulse wave and
carotid artery ultrasound
Long-term particle mass exposure:
Not appear to be associated with
greater arterial stiffness.
[75] Australian Cross-sectional 606 Ambient PM
2.5
,NO
2
Long-term exposure CCS PM
2.5
(per μg/m
3
increase):
Association: CCS (≥100): (OR 1.20,
95% CI: 1.02 to 1.43); CCS (≥400):
(OR 1.55, 95% CI: 1.05 to 2.29).
[76] Germany Cross-sectional 4291 Ambient PM
2.5
,PM
10
Long-term exposure Arterial blood pressure (BP) Per IQR of PM
2.5
(2.4 μg/m
3
):
Systolic BP increased by 1.4 mmHg
(95% CI: 0.5 to 2.3);
Diastolic BP increased by 0.9
mmHg (95% CI: 0.4 to 1.4).
[77] Switzerland Cross-sectional 1503 Ambient PM
10
,PM
2.5
,
UFP
Long-term exposure CIMT Vehicular source of PM
2.5
:
CIMT increased by 1.67% (95% CI:
-0.30 to 3.47%).
[78] USA Cross-sectional 6256 Ambient PM
2.5
(EC, OC,
silicon, and sulfur)
Long-term exposure CIMT, PM
2.5
components
EC, OC, silicon, and sulfur
Per IQR increase of PM
2.5
:
Association/increase: CIMT
PM
2.5
(14.7 μm, 95% CI: 9.0 to 20.5);
OC (35.1 μm, 95% CI: 26.8 to 43.3);
EC (9.6 μm, 95% CI: 3.6 to 15.7);
Sulfur (22.7 μm, 95% CI: 15.0 to
30.4).
[79] Seoul, Korea Cohort study 364 Ambient PM
2.5
Long-term exposure Coronary computed
tomographic angiography
PM
2.5
(per 1 μg/m
3
increase):
Increase/association: HRP (aHR 1.62,
Liang et al. Particle and Fibre Toxicology (2020) 17:61 Page 7 of 24
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Table 1 Epidemiological studies on the association between PM
2.5
exposure and atherosclerosis (Continued)
Reference Location Study design Sample size Pollutants PM
2.5
Exposure Evaluation index Findings or association
95% CI: 1.22 to 2.15, p < 0.001);
fibrofatty and necrotic core
component (aHR 1.41, 95% CI: 1.23
to 1.61, p < 0.001); total plaque
volume progression (aHR 1.14, 95%
CI: 1.05 to 1.23, p = 0.002).
[80] USA Cross-sectional 417 Ambient PM
2.5
,O
3
Long-term exposure CIMT PM
2.5
(per 1 μg/m
3
increase):
CIMT increased by 4.28 μm/y (95%
CI: 0.02 to 8.54μm/y).
[81] Germany Prospective
cohort
4494 Traffic and PM
2.5
Long-term exposure CAC Possible association between PM
2.5
exposure and CAC
[82] USA Cohort study 3506 Ambient PM
2.5
Long-term exposure TAC, AAC No consistent associations
between PM
2.5
and TAC, AAC
[83] Taiwan Prospective
cohort
30034 Ambient PM
2.5
Long-term exposure CRP PM
2.5
(per 5 μg/m
3
increase):
Association: systemic inflammation
CRP increased by 1.31% (95% CI:
1.00% to 1.63%)
[84] North Carolina Cross-sectional 861 PM
10
,PM
2.5
,NO
2
,O
3
- CIMT No associations between PM
2.5
and CIMT.
[85] Detroit, MI; Oakland, CA;
Pittsburgh, PA; Chicago,
IL; and Newark, NJ
Cohort study 1188 PM
2.5
,O
3
Long-term exposure CIMT, IAD, plaque presence
and plaque index
PM
2.5
(1 μg/m
3
higher 5-year
mean):
CIMT increased 8 μm (95% CI: 1.0
to 15.1), adjusting for
cardiovascular disease risk factors;
No significant associations
between PM
2.5
and IAD;
No associations between PM
2.5
and plaque presence or plaque
index.
[86] German Cohort study 4814 PM
2.5
,PM
10
Long-term
exposure
CIMT PM
2.5
(interdecile range increase
4.2μg/m
3
):
CIMT increased 4.3% (95% CI: 1.9%
to 6.7%);
PM
10
(interdecile range increase
6.7μg/m
3
):
CIMT increased 1.7% (95% CI: -0.7%
to 4.1%).
[87] Sichuan, China Longitudinal
study
205 Household air pollution
(PM
2.5
and BC)
Short-term exposure (48
h)
BP, PP, cfPWV, AIx PM
2.5
(1-ln (μg/m
3
) increase):
Association: SBP; PP; cfPWV (-0.1
m/s, 95% CI -0.4 to 0.2) with no
difference; slightly higher AIx (1.1%,
95% CI -0.2 to 2.4).
[88] Puno, Peru Cross-sectional 266 Householdbiomass fuel long-term
exposure
Measure 24 h indoor PM
2.5
,
CIMT, Carotid plaque, BP
Biomass fuel exposure:
Increased: CIMT (0.66 vs 0,60 mm,
p < 0.001); carotid plaque
prevalence (26% vs 14%, p < 0.05);
systolic BP (118 vs 111 mm Hg, p
< 0.001); median household PM
2.5
(280 vs 14 μg/m
3
, p < 0.001).
[39] Taiwan, China Prospective panel
atudy
117 Ambient PM
2.5
,NO
2
- baPWV, hsCRP PM
2.5
(10 μg/m
3
increases at 1 day
lag):
Liang et al. Particle and Fibre Toxicology (2020) 17:61 Page 8 of 24
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Table 1 Epidemiological studies on the association between PM
2.5
exposure and atherosclerosis (Continued)
Reference Location Study design Sample size Pollutants PM
2.5
Exposure Evaluation index Findings or association
Association: baPWV (2.1%, 95% CI:
0.7%-3.6%; 2.4%, 95% CI: 0.8%-
4.0%);
No significant association between
NO
2
and baPWV.
[89] USA Cross-sectional 798 PM
2.5
long-term
exposure
CIMT PM
2.5
(10 μg/m
3
increases):
CIMT increased (5.9%, 95% CI: 1 to
11%); Adjustment of age, never
smokers, ≥60 years of age
women: the strongest associations
with CIMT increased (15.7%, 95%
CI: 5.7 to 26.6%).
[90] USA Cross-sectional 1147 PM
2.5
long-term
exposure
calcium scores PM
2.5
(10 μg/m
3
):
Aortic calcification (RR=1.06; 95%
CI: 0.96 to 1.16);
Long-term residence near a PM
2.5
monitor (RR=1.10; 95% CI: 1.00 to
1.22).
[91] USA Cohort study 5172 PM
2.5
long-term
exposure
CIMT PM
2.5
(12.5 μg/m
3
increases):
CIMT increased 1 to 3%.
[81] Geman Prospective
cohort study
4494 PM
2.5
long-term
exposure
CAC PM
2.5
(3.91 μg/m
3
):
CAC higher 17.2% (95% CI: -5.6 to
45.5%).
[92] Hebei, China Cross-sectional 752 Indoor PM
2.5
, CO, SO
2
Long-term exposure CIMT, IL-8, CRP, TNF-α, SAA1 Smoky coal combustion-derived in-
door air pollutants:
Increased: systemic inflammation;
The risk of carotid atherosclerosis
RR = 1.434 (95% CI: 1.063 to 1.934,
p = 0.018).
Note: Short-term exposure means the period of exposure is less than 3 months; Long-term exposure means the period of exposure is longer than 3 months
AAC abdominal aortic calcium agatston score, aHR adjusted hazard ratio, AIx augmentation index, BC black carbon, BP Blood pressure, CAC coronary artery calcification, CCS Coronary artery calcium score, cfPWV
carotid-femoral PWV, CI confidence interval, CIMT carotid intima-media thickness, CRP C-reactive protein, EC elemental carbon, HDL-P high-density lipoprotein cholesterol particle matter, HOI HDL oxidant index, HDL-C
high-density lipoprotein cholesterol, HRP high-risk plaque, IAD inter-adventitial diameter, IMT intima-media thickness, IL interleukin, O
3
ozone, IQR interquartile, NO nitrogen dioxide, OC organic carbon, Ox-LDL oxidized
low-density lipoprotein, OR odds ratio, PM
2.5abs
absorbance levels of PM
2.5
,PNacc particle number of accumulation mode particles, PP pilse pressure, UFP ultrafine particles (< 0.1μm), TAC thoracic aortic calcium
agatston score, SBP systolic blood pressure, sCD36 soluble cluster of differentiation 36, sICAM-1 soluble Intercellular Adhesion Molecule-1, SO
2
sulfur dioxide, PWV Pulse wave velocity, baPWV brachial-ankle pulse
wave velocity
Liang et al. Particle and Fibre Toxicology (2020) 17:61 Page 9 of 24
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Table 2 Animal studies on the association between PM
2.5
exposure and atherosclerosis
Reference PM
2.5
source Mouse model Diet Exposure
Time
Findings
[94] Shanghai, China
Ambient PM
2.5
ApoE
-/-
mice Normal chow;
High-fat diet
8 h/day,
7 days/week,
16 weeks
PM
2.5
exposure induced and promoted
atherosclerotic lesions with significant
difference.
Increased:
Atherosclerotic plaque; lipids (ApoB, LDL-C,
T-CHO, TG); CD36; ox-LDL; inflammatory cy-
tokines (IL-1β, IL-18); NLRP3, caspase-1, ASC,
pro-caspase-1, cleaved-caspase-1;
Decreased:
Lipids (ApoA1 and HDL-C)
[95] Nanjing, China
Ambient PM
2.5
ApoE
-/-
mice High-fat diet 12 weeks PM
2.5
exposure amplified atherosclerotic
lesions with significant difference.
Increased:
Atherosclerotic plaque; lipid accumulation;
TC; LDL-C; Inflammatory cytokines (IL-6,
TNF-α);
Deceased:
Anti-inflammatory cytokines (IL-10, TGF-β);
CD4
+
CD25
+
Foxp3
+
Tregs; Foxp3
[96] Beijing, China
Ambient PM (PM
2.5
and
PM
10
)
ApoE
-/-
mice High-fat diet 24 h/day,
7 days/week,
2 months
PM
2.5
increased atherosclerotic plaque with
significant difference.
Increased:
Lesion area; TC; LDL; ox-LDL; visfatin; sys-
temic inflammation and pulmonary inflam-
mation response (IL-6, TNF-α); MDA
Decreased:
SOD; GSH-Px
[97] Beijing, China
Ambient PM (PM
2.5
and
PM
10
)
ApoE
-/-
mice High-fat diet 24 h/day,
7 days/week,
2 months
PM
2.5
exposure increased atherosclerotic
plaque with significant difference.
Increased:
Plaque area; TC; LDL; ox-LDL; systemic in-
flammation (Hs-CRP, IL-6, TNF-α) and pul-
monary inflammation response (IL-6, TNF-α);
Decreased:
T-AOC; SOD
[12] Michigan State
University, USA
Ambient PM
2.5
ApoE
-/-
or LDLR
-/-
mice
High-fat diet 6 h/day,
5 days/week,
6 months
PM
2.5
exposure increased atherosclerotic
plaque with significant difference.
Increased:
Lesion area; lipid and collagen content; 7-
KCh and uptake; CD36; foam cell formation
[51] Nanjing, China Ambient
PM
2.5
ApoE
-/-
mice High-fat diet twice/week,
12 weeks or 24
weeks
PM
2.5
exposure promoted atherosclerotic
plaque development and increased plaque
vulnerability, with significant difference.
Increased:
Lesion area, lipid; broken aortic elastic
fibers;
Decreased:
Collagen content; fibrous cap
[6] Beijing, China
Ambient PM
2.5
ApoE
-/-
mice High-fat diet Every 3 days,
2 months,
PM
2.5
exposure increased the formation of
atherosclerosis and the influence probably
persisted after 1-month recovery, with sig-
nificant difference.
Increased:
Atherosclerotic lesion; inflammatory
cytokines; lipid metabolism alteration.
[98] Tianjin, China
Traffic related PM
2.5
,
simulated PM
2.5
ApoE
-/-
mice High-fat diet Every two days,
10 weeks
Traffic related and simulated PM
2.5
promoted the formation of atherosclerosis
with significant difference.
Increased:
Plaque; T-CHO; LDL-C; TG; MDA;
Decreased:
HDL-C; SOD; GSH-Px
[99] Northeastern,
China
Ambient PM
2.5
, WDE,
DEG
ApoE
-/-
mice
Normal chow average of 5.2
hours/day, 4
days/week, 3
months and 5
months
Exposure to PM
2.5
for 5 months induced
atherosclerotic plaques with significant
difference.
For plaque exacerbation, PM
2.5
> WDE >
DEG = FA
Increased:
Plaque; vasomotor dysfunction;
inflammation
Liang et al. Particle and Fibre Toxicology (2020) 17:61 Page 10 of 24
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
progression of advanced atherosclerotic lesions. Concen-
trated ambient PM
2.5
, rather than whole diesel exhaust
and diesel exhaust gases, is mainly responsible for plaque
exacerbation [99]. However, an improved understanding
of which components of PM
2.5
induce or promote the de-
velopment of atherosclerosis, which may be a direction of
future research, is needed. Mechanistically, changes in oxi-
dative stress, systematic inflammation and lipid
metabolism are the most common mechanisms of PM
2.5
-
induced atherosclerosis. The mechanisms of atheroscler-
osis induced by PM
2.5
have been reviewed [105]. Oxidative
stress induced by particulate matter may be key to trigger-
ing the development of atherosclerosis, coagulation and
thrombosis [106,107]. Endothelial dysfunction is a critical
initiating event that promotes the development of athero-
sclerosis. However, a systematic understanding of the
Table 2 Animal studies on the association between PM
2.5
exposure and atherosclerosis (Continued)
Reference PM
2.5
source Mouse model Diet Exposure
Time
Findings
[100] Yinchuan, China coal-
fired PM
2.5
C57BL/6J mice
and ApoE
-/-
mice
High-fat diet 3 h/day,
1 day/week,
8 weeks
Coal-fired PM
2.5
significantly promoted the
formation atherosclerosis with significant
difference.
Increased:
Plaque; foam cells; fibrous cap formation;
ET-1; ICAM-1; E-selectin
Decreased:
vWF
[101] Manhattan,
USA
PM
2.5
ApoE
-/-
mice Normal chow
and High-fat diet
6 h/day,
5 day/week,
6 months
In high-fat diet group, PM
2.5
increased
plaque area compared with FA (p < 0.01);
In normal chow group, PM
2.5
increased
plaque area compared with FA (p < 0.15).
Increased:
Plaque area; Cholesterol; Constriction
response; CD68; 3-Nitrotyrosine; eNOS;
iNOS;
Decreased:
Relaxation response
[102] Los Angeles freeway,
USA
PM
2.5
ApoE
-/-
mice regular diet 5 h/day,
3 day/week,
75 hours
PM
2.5
resulted in aortic atherosclerotic
lesion increased trend (p = 0.1).
Increased:
Plaque area; Liver MDA;
Decreased:
HDL anti-inflammatory properties
[103] New York; USA
PM
2.5
C57BL/6, ApoE
-/-
mice, ApoE and
LDLR double
knockout (DK)
High-fat diet and
regular diet
6 h/day,
5 day/week,
5 months
PM
2.5
exposure increased atherosclerotic
lesion in ApoE
-/-
mice (p < 0.05).
Atherosclerotic lesion 57% increase in
ApoE
-/-
mice; Atherosclerotic lesion 10%
increase in male DK mice and 8% decrease
in female DK mice.
[104] New York; USA
PM
2.5
ApoE
-/-
mice High-fat diet 30 mg/kg/day, 8
weeks
PM
2.5
contributed to the progression of
atherosclerosis (p < 0.05).
Increased:
Atherosclerotic plaques; numbers of lesion
macrophages; endothelial layer injury;
platelets and leukocytes adherence; IL-6;
TNF-α; iNOS; IL-12; arginase-1; CD206
[26] DEP, 1650b, NIST, USA C57BL/6,
ApoE
-/-
mice
Regular chow or
high-fat diet
Once a day
during 5 days/
week, 3-6 weeks
DEP exposure increased atherosclerotic
lesion in ApoE
-/-
mice (p < 0.05).
Increased:
Atherosclerotic plaques; EPC apoptosis;
superoxide production;
Decreased:
Neoangiogenesis; EPC migration;
Endothelial cell interity
[25] DEP, SRM-2975, NIST,
USA
C57BL/6,
ApoE
-/-
mice
Regular chow or
high-fat diet
Twice weekly
instillation
DEP exposure increased atherosclerotic
lesion in ApoE
-/-
mice (p < 0.05).
Increased:
Atherosclerotic plaques; Cholesterol;
antioxidant genes in the liver
Note: Apo A1 apolipoprotein A1, Apo B apolipoprotein B, ASC apoptosis associated speck like protein, CD36 cluster of differenti ation 36, DEG diesel exhaust gases,
DEP Diesel exhaust particles, ET-1 endothelin-1, eNOS endothelial nitric oxide synthase, FA filtered air, Foxp3 forkhead box transcription factor P3, GSH-Px
glutathione peroxidase, HDL-C high density lipoprotein-cholesterol, Hs-CRP high sensitive C-reactive protein, IL interleukin, ICAM-1 Intercellular Adhesion Molecule-
1, iNOS inducible nitric oxide synthase, 7-KCh 7-ketocholesterol, LDL-C low density lipoprotein-cholesterol, MDA malondialdehyde, NIST National Institute of
Standards and Technology, NLRP3 NOD-like receptor protein 3, ox-LDL oxidized low-density lipoprotein, PM particulate matter, SOD superoxide dismutase, T-AOC
total antioxidant capacity, T-CHO total cholesterol, TG triglycerides, TGF-βtransforming growth factor-β,TNF-αtumor necrosis factor α,vWF von willebrand factor,
WDE whole diesel exhaust
Liang et al. Particle and Fibre Toxicology (2020) 17:61 Page 11 of 24
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
mechanisms underlying PM
2.5
-induced endothelial dys-
function leading to atherosclerosis is lacking.
Ambient PM
2.5
induces endothelial dysfunction
The endothelial cell monolayers of blood vessels play a
role in exchanging macromolecules between the blood
and tissues. Mechanical stimuli such as shear stress, in-
flammatory cytokines and angiotensin-II (Ang-II) affect
endothelial permeability [108,109]. We concentrated on
studies indicating that PM
2.5
impacts vascular endothe-
lial dysfunction. Many studies have demonstrated that
PM
2.5
increases the vascular permeability, impairs endo-
thelial vasomotor function and vascular reparative cap-
acity via different mechanisms and occurs before vascular
diseases such as atherosclerosis. Traffic-derived emissions
are a major source of ambient PM
2.5
; therefore, literature
on the toxicity of traffic emissions (mainly DEPs) on blood
vessels and endothelial cells and the similarities between
PM
2.5
and DEPs are also discussed in this review. The ef-
fects of PM
2.5
and DEPs on endothelial cells are shown in
Table 3. In brief, the existing evidence shows that PM
2.5
and DEPs both consistently induces endothelial cytotox-
icity through similar mechanisms, such as by increasing
endothelial cellular apoptosis via oxidative stress or au-
tophagy, reducing the migration of endothelial cells and
enhancing vascular endothelial permeability [111,117,
118,122,123]. The detailed mechanisms of endothelial
cytotoxicity induced by PM
2.5
or traffic-derived pollutants
are discussed below. In addition, coal-fired PM
2.5
also de-
creases endothelial viability; however, the detailed mecha-
nisms are limited to increases in DNA methylation and
oxidative DNA damage in EA.hy926 cells [128].
Ambient PM
2.5
increases vascular endothelial
permeability
The proposed mechanism of PM
2.5
-triggered vascular
endothelial permeability increase is presented in Fig. 2a.
In Balb/c mice exposed to low-dose (1.27 mg/kg) and
high-dose (6.34 mg/kg) PM
2.5
through the tail vein for
48 h, PM
2.5
destroyed the integrity of vessels, as assessed
by the Evans blue infiltration assay, and the results con-
firmed that PM
2.5
increased vascular permeability in vivo
[114]. DEPs increase vascular endothelial permeability
by downregulating the expression of zonula occludens-1
(ZO-1, a tight junction protein) [123]. Ambient PM
2.5
exposure disrupts the balance between antioxidation and
oxidation in vascular endothelial cells, leading to in-
creased permeability of the endothelial monolayer. Epi-
demiological evidence has shown that exposure to PM
2.5
reduces the anti-inflammatory and antioxidant capacity
of high-density lipoprotein (HDL), and decreases the ex-
pression of antioxidant markers such as glutathione per-
oxidase (GSH) and superoxide dismutase (SOD) [67,
129]. A review showed that particulate matter impairs
HDL function via oxidative pathways [53]. Importantly,
evidence has shown that exercise training enhances
HDL functions, including cholesterol efflux capacity and
antioxidant capacity, and protects against endothelial
dysfunction induced by PM
2.5
[130]. PM
2.5
decreases the
mitochondrial membrane potential, increases reactive
oxygen species (ROS) generation, and causes oxidative
stress, inflammation and apoptosis in EA.hy926 cells and
human umbilical vein endothelial cells (HUVECs) [110,
115,124]. ROS play important roles in inflammatory re-
sponses, apoptosis, and cell growth, as well as in the oxi-
dation of LDL cholesterol [131]. PM
2.5
induces ROS
generation and endothelial cell apoptosis through the
mitochondrial pathway in EA.hy926 cells [132]. PM
2.5
induces cell autophagy and apoptosis via endoplasmic
reticulum (ER) stress in EA.hy926 cells and HUVECs
[111]. Although normal autophagy seems to protect cells
from PM
2.5
-triggered apoptosis, PM
2.5
blocks autophagic
flux and then robustly aggravates endothelial cell apop-
tosis [111,122,127]. Effective inhibition of ER stress
using 4-PBA (an ER stress inhibitor) contributes to the
alleviation of PM
2.5
induced cell apoptosis and the ex-
pression of LC3II [111]. Bafi A1 (an autolysosome in-
hibitor) aggravates PM
2.5
-induced cell apoptosis by
disrupting autophagic flux [111]. Exposure to PM
2.5
in-
duces activation of the inflammatory cyclooxygenase-2
(COX-2)/prostaglandin E synthase (PGES)/prostaglandin
E 2 (PGE2) axis and promotes the inflammatory re-
sponse and apoptosis in mouse aorta endothelial cells
(MAECs) [121]. Excessive apoptosis triggers an increase
in transcellular permeability in the vascular endothelial
monolayer [133]. Ambient PM
2.5
disrupts iron uptake
and storage by regulating the expression of transferrin
receptor (TFRC), ferritin light chain (FTL) and heavy
chain (FTH1), causing intracellular iron overload and
subsequently provoking ferroptosis in EA.hy926 cells
and HUVECs [112]. PM
2.5
induces ROS production and
lipid peroxidation in endothelial cells and increases
membrane permeability [112,134]. Furthermore, PM
2.5
induces senescence associated-βgalactosidase (SA-β-gal)
activation via redox sensitivity of the local angiotensin
system in premature coronary arterial endothelial cells
(PCAECs), leading to endothelial senescence [113]. The
presence of senescent endothelial cells in a nonsenescent
monolayer disrupts the tight junction morphology of
surrounding young cells and increases the permeability
of the monolayer [135].
Vascular endothelial (VE)-cadherin is largely expressed
on endothelial cell membranes. The extracellular domain of
VE-cadherin mediates endothelial cell-to-cell adhesion
through hemophilic trans interactions, whereas its cytoplas-
mic tail associates with the actin cytoskeleton, strengthen-
ing the adhesion junction between endothelial cells [136].
Liang et al. Particle and Fibre Toxicology (2020) 17:61 Page 12 of 24
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Table 3 PM
2.5
exposure in endothelial cells
Reference Endothelial
cells lines
PM
2.5
source Exposure concentration PM
2.5
Exposure
time
Evaluation
[110] EA.hy926 Beijing, China Urban
PM
2.5
PM
2.5
: 2, 10, 40, 100, 200, 1000 μg
/cm
2
;
SOD (ROS scavenger): 0.5 mg/ml.
24 h Trace elements in PM
2.5
suspension, water-
insoluble and water-soluble;
Cell viability; ROS; MMP; Apoptosis.
[111] EA.hy926,
HUVECs
PM
2.5
SRM1648a, NIST, USA
PM
2.5
: 1.25, 2.5, 5, 10, 20, 40 μg /cm
2
;
4-PBA (ER stress inhibitor): 1 mM; 3-
MA (a classical PI3K III inhibitor, au-
tophagy antagonist): 2.5 mM; Rapa
(an mTOR inhibitor, autophagy agon-
ist): 50 nM; Bafi A1 (a proton-pump
inhibitor, autolysosome inhibitor): 20
nM.
24 h Cell viability; ER stress; Autophagy; Apoptosis;
Autophagic flux.
[112] EA.hy926,
HUVECs
PM
2.5
SRM1648a, NIST, USA
PM
2.5
: 1.25, 2.5, 5, 10, 20, 40 μg/cm
2
;
Fer-1 and DFOM (ferroptosis
inhibitors): 500 nM and 5 μM,
respectively.
24 h or 12 h Cell viability; intracellular iron content; GSH;
lipid peroxidation; redox imbalance;
ferroptosis-related genes or biomarkers.
[113] PCAECs Fine dust, ERM-CZ100,
Sigma-Aldrich, USA
Fine dust: 1, 3, 10, 30, 100 μg/ml;
NAC: 10 mM; Losartan: 10 μM.
48 h or 1, 4, 24 h SA-β-gal; platelet aggregation; cell
proliferation; Oxidative stress; Relaxation;
Senescence.
[114] HUVECs Beijing, China PM
2.5
: 2, 20, 100 μg/ml;
NAC: 5 mmol/l
6, 12, 24 h VE-cadherin; VEGFR2 and MAPK/ERK signaling;
ROS; SOD.
[108] HUVECs Beijing, China PM
2.5
:80μg/ml;
miR-21 inhibitor
24 h miR-21; target genes; VE-cadherin.
[115] HUVECs Mexico PM
2.5
:20μg/cm
2
; 3, 24, 48, 72 h Oxidative stress; NF-κB; Apoptosis.
[116] HUVECs Wuhan, China PM
2.5
: 6.25, 12.5, 25 μg/ml;
SP600125 (JNKs inhibitor);
SB203580 (p38K inhibitor);
PD98059 (ERKs inhibitor);
24 h AP-1; Oxidative stress; pro-inflammatory
response.
[117] HUVECs,
HMEC-1
PM
2.5
NIST, USA
PM
2.5
: 100, 200, 400, 800 μg/ml; 24 h Cell viability; Apoptosis; Migration; Tube
formation; ROS; Inflammation.
[118] EA.hy926 Yuquan Road, Beijing,
China
PM
2.5
: 25, 50, 100, 200 μg/ml;
SP600125 (JNK inhibitor): 25 μM;
U0126 (ERK inhibitor): 10μM;
SB203580 (p38 MAPK inhibitor):
25μM; LY294002 (PI3K/AKT inhibitor):
25μM; BAY11-7082 (NF-kB inhibitor):
5μM.
1, 3, 6, 12, 24 h Cell viability; ROS; Adhesion molecule;
Adhesion experiment.
[119] HUVECs COFs-derived PM
2.5
PM
2.5
: 12.5, 25, 50, 75, 100, 200μg/ml;
SU5416 (a VEGFR2 inhibitor): 0.5, 1,
2.5, 5, 7.5, 10, 20 μM.
12, 24, 36 h Cell viability; Tube formation.
[120] HUVECs Taiyuan, China PM
2.5
:1,5,10μg/ml;
Pam3CSK4 (TLR2 agonist): 1μg/ml;
LPS (TLR4 agonist): 500μg/ml; anti-
TLR2 (TLR2 inhibitor): 10μg/ml;
12 h Inflammation.
Liang et al. Particle and Fibre Toxicology (2020) 17:61 Page 13 of 24
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Table 3 PM
2.5
exposure in endothelial cells (Continued)
Reference Endothelial
cells lines
PM
2.5
source Exposure concentration PM
2.5
Exposure
time
Evaluation
TAK242 (TLR4 inhibitor): 5μmol/l.
[121] MAECs Wuhan, China PM
2.5
: 25, 50, 100 μg/ml;
NS-398 (COX-2 inhibitor): 10μM.
12, 24 h Apoptosis.
[122] HUVECs,
ATG12-KO
HUVECs
Diesel exhaust particles
(DEP)
DEP: 25, 50 μg/ml;
NAC: 5 mM; Nutllin-3a: 5 μM;
PMA (ROS inducer): 1μM
2, 4, 8, 24 h Cell viability; ROS; Cytokeleton; Lysosome;
Apoptosis; DNA damage; Tube formation;
Migration; Autophagy.
[123] HAECs DEP DEP: 12.5, 25, 50μg/ml; 2, 4, 6 h Permeability; LDH; Apoptosis; ZO-1.
[124] HUVECs Non-industry district,
Shanghai, China
PM
2.5
: 100, 200, 400 μg/ml;
Atorvastatin: 0.1, 1, 10 μmol/l.
24 h Water-soluble and organic extracts; Cell
viability; Oxidative stress; Cytokines.
[125] HCAECs Southern Taiwan PM
2.5
: 20, 50 μg/ml; 4 h Metal fume particles; Cell viability; 8-OHdG; IL-
6; NO.
[126] HUVECs Mexico PM
2.5
: 5, 10, 20, 40 μg/cm
2
;
TNF-α: 10 ng/ml.
6 or 24 h Cell viability; Adhesion; Adhesion molecules.
[127] HUVECs Beijing, China PM
2.5
: 5, 25, 50, 100, 200 μg/ml;
Rap: 100 nmol/l; 3-MA: 5 mmol/l.
24 h Cell viability; Autophagosome; Autophagy.
[128] EA.hy926 Coal-fired PM
2.5
(Yinchuan, Datong,
Jingxi, Zhijin, China)
PM
2.5
: 10, 25, 50 μg/ml; 24 h Cell viability; DNA methylation; DNA damage.
Note: AP-1 activation protein-1, Bafi A1 Bafilomycin A1, DEP Diesel exhaust particles, DFOM Deferoamine mesylate, EA.hy926 human umbilical vein cell line, ER endoplasmic reticulum, ERK extracellular signal-regulated
kinase, Fer-1 Ferrostatin-1, GSH glutamate, HCAECs human coronary artery endothelial cells, HMEC-1 human microvascular endothelial cells, IL interleukin, LDH lactate dehydrogenase, MAECs Mouse aorta endothelial
cells, 3-MA 3-Methyadenine, MAPK mitogen-activated protein kinase, MMP Mitochondrial membrane potential, NAC N-acetyl-L-cysteine, NF-κBnuclear factor kappa-B, NIST National Institute of Standards and
Technology, NO nitric oxide, 8-OHdG 8-hydroxy-2’-deoxyguanosine, PAH polycyclic aromatic hydrocarbon, 4-PBA 4-phenylbutyrate, PMA Phorbol-myristate-acetate, Rapa/Rap Rapamycin, ROS reactive oxygen species, SA-
β-gal Senescence-associated (beta)-galactosidase, TNF-αtumor necrosis factor α,VE-cadherin vascular endothelial cadherin, VEGFR2 vascular endothelial growth factor receptor 2, VOC volatile organic compounds, ZO-1
Zonular Occludin-1
Liang et al. Particle and Fibre Toxicology (2020) 17:61 Page 14 of 24
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Thus, VE-cadherin plays a key role in maintaining endothe-
lial barrier integrity, controlling the transmembrane move-
ment of macromolecule substances such as blood cells.
PM
2.5
induces the phosphorylation of vascular endothelial
growth factor receptor 2 (VEGFR2) on the endothelial cell
membrane and activates downstream mitogen-activated
protein kinase (MAPK)/extracellular signal-regulated kinase
(ERK) signaling, leading to the shedding of adhesion con-
nexin VE-cadherin [114]. PM
2.5
induces endothelial cell
cytoskeleton rearrangement via Rho-dependent pathways
to facilitate vascular hyperpermeability [137]. Targeting of
tissue inhibitor of metalloproteinase 3 (TIMP3)/MMP9 and
VE-cadherin by miR-21 in response to PM
2.5
increases vas-
cular endothelial cell permeability in HUVECs [108]. In-
flammation stimulates a series of signaling pathways that
reduce the level of VE-cadherin expressed or induces VE-
cadherin phosphorylation and then destroys the adhesion
structure [138].
Fig. 2 Summary of the main mechanisms of PM
2.5
-caused vascular endothelial injury. Mainly involved three aspects: a.PM
2.5
increased vascular
endothelial permeability; b.PM
2.5
impaired vasomotor function; c.PM
2.5
declined vascular reparative capacity
Liang et al. Particle and Fibre Toxicology (2020) 17:61 Page 15 of 24
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Ambient PM
2.5
impairs vasomotor function
Endothelin-1 (ET-1) is a protein primarily produced by
endothelial cells that regulates cell proliferation and vas-
cular tone by activating its receptors, including type A
(ET
A
) and type B (ET
B
)[139]. Evidence has indicated
that inflammation, ischemia and hypoxia stimulate the
expression of ET-1 and its receptors [140]. Qinghua Sun
et al. exposed ApoE
-/-
mice to concentrated ambient
PM
2.5
for 6 months and assessed the vasoconstriction of
aortic rings in response to phenylephrine and serotonin
and vasorelaxation in response to acetylcholine. The re-
sults demonstrated that PM
2.5
significantly increased the
constriction of the aorta, especially in high-fat diet-fed
mice [101]. The proposed mechanism of by which PM
2.5
causes endothelial vasomotor function impairment is
presented in Fig. 2b. PM
2.5
elevates the circulating levels
of AngII, locally activates the AngII/AngII type 1 recep-
tor (AT1R) axis and activates phospholipase C (PLC)
and protein kinase C (PKC), promoting ET-1 biosyn-
thesis in HUVECs [116]. ET-1 is released from endothe-
lial cells, acts on the endothelial ET
B
receptor and
increases nitric oxide (NO) production [141]. The pro-
duction of NO by endothelial cells contributes to regu-
lating vasomotor tone. NO cats on circulating blood
platelets, leukocytes and adjacent smooth muscle cells
and reduces smooth muscle cell contractility [142].
PM
2.5
impairs the balance of vasorelaxation by oxidative
stress, and superoxide radicals combine with NO to
form peroxynitrite, thus reducing NO bioavailability in
the vessel wall [143]. Furthermore, PM
2.5
upregulates
the expression of ET
B
and ET
A
receptors in rat coronary
arteries [144]. ET
B
in vascular endothelial cells mediates
the vasodilation, while ET
A
and ET
B
in vascular smooth
muscle cells mediate the contractility, especially ET
A
ac-
tivation, which plays a greater role in coronary vasocon-
striction [141]. ET-1 in the vasculature causes brief
vessel relaxation due to ET
B
activation in endothelial
cells. However, this effect is quickly reversed by ET-1
binding to ET
A
, which reduces NO production in vascu-
lar smooth muscle cells and leads to the well-known
constrictive effects of ET-1 in the vasculature [145].
Therefore, PM
2.5
upregulates the expression of ET
B
and
ET
A
receptors in coronary arteries, but PM
2.5
mainly in-
creases vasoconstriction and contributes to the progres-
sion of atherosclerosis. AngII enhances ET-1-mediated
vasoconstriction by upregulating the expression of ET
A
in VSMCs [146]. In addition, PM
2.5
exposure causes vas-
cular insulin resistance and suppresses insulin-stimulated
endothelial nitric oxide synthase (eNOS) phosphorylation
(likely an endothelial-specific event) [147]. Insulin stimu-
lates the phosphorylation of eNOS and increases eNOS
activity and NO production [148–150]. Therefore, PM
2.5
-
provoked endothelial insulin resistance could be a key
event in regulating vascular tone. In brief, PM
2.5
shifts the
balance of vasomotor tone towards vasoconstriction by in-
creasing the levels of ET-1 and its receptors, as well as de-
creasing NO production and bioavailability. Exercise
training effectively prevents the imbalance in vasomotor
function triggered by PM
2.5
[130].
Ambient PM
2.5
suppresses vascular endothelial repair
Endothelial progenitor cells (EPCs), a group of stem cells/
progenitor cells, settle in the adult bone marrow and can
mobilize to the peripheral blood, home to sites of vascular
injury, proliferate and differentiate into endothelial cells,
and facilitate vascular recovery [151]. In addition to exert-
ing antioxidative and anti-inflammatory effects, HDL pro-
tects EPCs by increasing eNOS levels and decreasing
MMP9 levels, thereby reducing the apoptosis of EPCs
[152]. Bone marrow-derived EPCs from C57BL/6 mice ex-
posed to PM
2.5
inhalation for 9 or 30 days were injected
into unexposed mice subjected to hind limb ischemia and
vascular perfusion was assessed by laser Doppler perfusion
imaging (LDPI). The results confirmed that PM
2.5
signifi-
cantly impaired angiogenesis and that bone marrow-
derived EPCs have vascular reparative capacity in vivo
[153]. The proposed mechanism of PM
2.5
-triggered vascu-
lar repair suppression is presented in Fig. 2c. In C57BL/6
mice exposed to concentrated PM
2.5
inhalation for 9 or 30
consecutive days (6 h/day), PM
2.5
impaired endothelial pro-
genitor cellular differentiation and mobilization through
vascular insulin resistance and nuclear factor kappa-B (NF-
κB) and inflammasome activation, while insulin sensitizers
prevented PM
2.5
-triggered vascular insulin resistance and
inflammation and decreased circulating EPCs [154]. ROS
and inflammation suppress the proliferation of EPCs and
enhance the apoptosis of EPCs [155]. Furthermore, PM
2.5
decreases the abundance of EPCs, and impairs EPC func-
tions and prevents EPC-mediated vascular endothelial re-
covery associated with vascular endothelial growth factor
(VEGF) resistance and a decrease in NO bioavailability
[153]. In addition to EPCs, the proliferation and migration
abilities of mature endothelial cells are additional important
factors in endothelial injury repair. Endothelial cell prolifer-
ation and migration are initially required for arterial repair
after injury [156]. PM
2.5
decreases the viability and sup-
presses the proliferation and migration of HUVECs and hu-
man microvascular endothelial cells through oxidative
stress [117]. In brief, PM
2.5
disrupts two major factors in-
volved in repairing vascular endothelial damage: a. the
abundance and function of EPCs and b. the proliferation
and migration abilities of endothelial cells.
Ambient PM
2.5
-triggered endothelial injury and
atherosclerosis
Ambient PM
2.5
causes a pro-coagulant state
Atherosclerosis is characterized by the accumulation of
inflammatory cells and lipids in the walls of arteries. The
Liang et al. Particle and Fibre Toxicology (2020) 17:61 Page 16 of 24
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
intact endothelial cell layer exerts the first defense to
hinder the development of atherosclerosis. Endothelial
cell-derived mediators take part in hemostasis, including
tissue factor (TF), tissue factor pathway inhibitors
(TFPI), thrombomodulin (TM), and von Willebrand fac-
tor (vWF) [157,158]. For example, normal vascular
endothelium-synthesized TFPI regulates the balance be-
tween coagulation and fibrinolysis [44]. Exposure to air
pollution affects each of these dynamic processes, and
increasing evidence suggests that the balance of between
platelet activation, coagulation and fibrinolysis shifts to-
wards a pro-coagulant and anti-fibrinolytic state [8].
Sprague-Dawley (SD) rats were exposed to PM
2.5
(1.8,
5.4, 16.2 mg/kg bw) by intratracheal instillation every
three days for 30 days, and the results showed that
PM
2.5
increased the expression of TF in the vessel wall
and activated coagulation factors VII and X and the for-
mation of thrombin [158–160]. PM
2.5
reduces the ex-
pression of TM in the vascular endothelial monolayer,
thereby decreasing anti-coagulant function [160]. vWF is
mainly released by activated endothelial cells, which
bridge platelets and aggregates in the injured vessel walls
[161]. PM
2.5
downregulates the expression of vWF in the
serum and promotes the adherence of platelets to in-
jured endothelial layers, implying that vWF is consumed
during the process of platelet aggregation after exposure
to PM
2.5
[104,160]. Platelet adhesion, aggregation and
coagulation are implicated in inflammatory pathologies
of atherosclerosis [162,163].
Ambient PM
2.5
induces an inflammatory response
Short-term exposure to PM
2.5
induces systemic inflam-
mation and increases the circulation levels of inflamma-
tory biomarkers such as CRP, tumor necrosis factor α
(TNF-α), IL-6, IL-8 and MCP-1 [35,164]. PM
2.5
triggers
the secretion of IL-6 and IL-1βby activating the TLR-
mediated pathway in HUVECs, while TLR2 and TLR4
inhibitors reduce the PM
2.5
-triggered inflammatory re-
sponse [120]. PM
2.5
triggers endothelial activation, in-
creases the expression of adhesion molecules (ICAM-1
and VCAM-1) and induces THP-1 cell adhesion to
endothelial cells through the ERK/AKT/NF-κB-
dependent pathway in EA.hy926 cells; moreover, ERK/
AKT/NF-κB inhibitors have been used to demonstrate
the abovementioned effects [118]. Monocytes in the
blood adhere to endothelial cells through adhesion mol-
ecules and then migrate into the vascular wall [126,
165]. Monocytes that enter the blood vessel wall trans-
form into macrophages, which clear lipids and dead or
dying cells [166]. Exposure of ApoE
-/-
or LDLR
-/-
mice
to concentrated ambient PM
2.5
for 6 months (6 h/day, 5
days/week) showed that PM
2.5
significantly increases the
expression of CD36 in plaque macrophages, increases
the internalization of ox-LDL and mediates macrophage-
derived foam cell formation [12]. Both macrophage-
derived foam cells and necrotic cells release various in-
flammatory factors (such as TNF, IL-1, and IL-6),
thereby expanding the inflammatory response cascade
and inducing persistent inflammation in local blood ves-
sels [166]. Moreover, evidence from animal experiments
has shown that inflammation is significantly unregulated
in ApoE
-/-
mice after exposure to PM
2.5
(10 mg/kg bw)
for two months and that inflammation increases even if
PM
2.5
exposure is stopped [6]. The above evidence fo-
cuses on the effects of PM
2.5
on inflammation and
atherosclerosis.
Ambient PM
2.5
promotes lipid deposition
Lipid deposition is one of the key factors promoting the
development of atherosclerosis, especially ox-LDL de-
position, which contributes to necrotic core formation.
In the past few decades, lowering lipid levels has been
the main strategy for the treatment of atherosclerosis
[167]. However, currently, two views about how lipids
enter and deposit in the vascular wall are held. It has
been believed that damaged vascular walls cause LDL in-
filtration into the vascular wall and induce the develop-
ment of atherosclerosis [168]. Professor Shaul holds a
different view, suggesting that the receptor scavenger re-
ceptor type B1 (SR-B1) on endothelial cells has a trans-
cytosis effect on LDL and promotes the accumulation of
LDL in the vascular wall [169]. Lectin-like oxidized low-
density lipoprotein receptor-1 (LOX-1) is expressed in
endothelial cells, monocytes/macrophages and vascular
smooth muscle cells and is essential for binding to
oxLDL [170]. Pro-inflammatory and pro-oxidant, and
mechanical stimuli including ox-LDL, TNF-α, Ang II
and shear stress, can rapidly activate the expression of
LOX-1 [171]. In endothelial cells, LOX-1 activation in-
duces inflammation, reduces eNOS activation and NO
availability, and triggers endothelial dysfunction [172].
Ox-LDL induces the release of the soluble form of LOX-
1 (sLOX-1) from endothelial cells into the circulation
and the level of sLOX-1 correlates with carotid plaque
inflammation and risk for ischemic stroke [173]. Inhaled
vehicle emissions trigger significant increases in plasma
sLOX-1 levels in humans and mediate the upregulation
of ET-1 and MMP9 expression via ox-LDL-LOX-1 re-
ceptor signaling, further inducing vascular effects [174].
LOX-1 protein levels are increased in the aorta after
coexposure to ozone and DEPs [175]. Moreover, in
ApoE
-/-
mice exposed to a mixture of gasoline and diesel
engine exhaust (MVE), the expression of LOX-1 was in-
creased in cerebral microvascular endothelial cells, and
at least in part, MVE altered the structure and integrity
of the brain microvasculature via LOX-1 signaling [176].
Many studies have demonstrated that PM
2.5
contributes
to lipid dysregulation in the sera of ApoE
-/-
mice and
Liang et al. Particle and Fibre Toxicology (2020) 17:61 Page 17 of 24
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
promotes macrophage engulfment of ox-LDL through
surface scavenger receptors to induce foam cell forma-
tion [6,12,177]. However, studies on the effect of PM
2.5
on lipid uptake and transport in endothelial cells are
lacking, although limited evidence has shown that
traffic-derived pollutants increase LOX-1 signaling in
endothelial cells. In addition to inflammation, lipid up-
take and transport are key factors in the development of
atherosclerosis. Thus, the effect of PM
2.5
on the binding
of ox-LDL to endothelial cells is an area of intense
investigation.
Indoor PM
2.5
elicits endothelial dysfunction and
atherosclerosis
WHO data has shown that more than 41% of households
are still using solid fuels and kerosene for cooking, produ-
cing harmful smoke in the home and causing the death of
approximately 916 thousand individuals from cardiovas-
cular disease [178]. CIMT is a marker of subclinical ath-
erosclerosis. Recently, epidemiological evidence showed
that PM
2.5
emissions from biomass cooking fuel in peri-
urban villages of India were positively associated with in-
creased CIMT [61]. Consistent with this study, Matthew S
Painschab et al. also showed that indoor PM
2.5
sourced
from biomass fuel in Puno, Peru, was associated with
CIMT, an enhanced prevalence of atherosclerotic plaque
and increased blood pressure [88]. In the rural villages of
Sichuan, China, household PM
2.5
from biomass stoves is
associated with central hemodynamics and increased
blood pressure; however, it is not associated with pulse
wave velocity (PWV, a marker of arterial stiffness) [87]. In-
door particles impair microvascular function through in-
flammation and oxidative stress [179]. Cooking oil fumes
(COFs), the main pollutants in kitchen air, can signifi-
cantly reduce cellular viability, and inhibit angiogenesis in
HUVECs through the ROS-mediated NLRP3 inflamma-
some pathway or VEGF/VEGFR2/MEK1/2/ERK1/2/
mTOR pathway [40,119]. COF-derived PM
2.5
mediates
autophagy via the ROS/AKT/mTOR axis in HUVECs
[180]. Evidence for the mediating role of indoor PM
2.5
in
vascular endothelial dysfunction is limited.
Conclusion
In summary, PM
2.5
exposure is positively associated with
atherosclerosis based on epidemiological evidence. Epi-
demiological and animal experimental evidence has estab-
lished that PM
2.5
-induced atherosclerosis is mainly
mediated by inflammation and lipid metabolism alter-
ations. On the basis of in vivo and in vitro studies, PM
2.5
induces vascular endothelial dysfunction and a procoagu-
lant state and increases inflammation and lipid abnormal-
ities, thus promoting the development of atherosclerosis.
However, only a few studies have tried to explore prevent-
ive measures. It would be meaningful to explore measures
or targets that can contribute to the prevention of PM
2.5
-
induced endothelial dysfunction or atherosclerosis, which
remains to be solved before the environment improves.
Changes occur at the molecular level significantly earlier
than histopathology and clinical symptoms. Consequently,
improving the understanding of molecular mechanisms
will be helpful in preventing the occurrence or develop-
ment of atherosclerosis, or identifying potential thera-
peutic targets for atherosclerosis treatment.
Abbreviations
AAC: Abdominal aortic calcium agatston score; ABCA1: ATP-binding cassette
transporter A1; AngII: Angiotensin II; aHR: Adjusted hazard ratio; AT1R: AngII
type 1 receptor; AIx: Augmentation index; ApoA1: Apolipoprotein A1;
ApoB: Apolipoprotein B; AP-1: Activation protein-1; ASC: Apoptosis associated
speck like protein; Bafi A1: Bafilomycin A1; BC: Black carbon; BP: Blood
pressure; baPWV: Brachial-ankle pulse wave velocity; CAC: Coronary artery
calcification; CCS: Coronary artery calcium score; CD36: Cluster of
differentiation 36; cfPWV: Carotid-femoral PWV; CI: Confidence interval;
CIMT: Carotid intima-media thickness; COFs: Cooking oil fumes; COX-
2: Cyclooxygenase -2; CRP: C-reactive protein; DEG: Diesel exhaust gases;
DFOM: Deferoamine mesylate; EA.hy926: Human umbilical vein cell line;
EC: Elemental carbon; eNOS: Endothelial nitric oxide synthase;
EPC: Endothelial progenitor cells; ET-1: Endothelin-1; ET
A
: Endothelin type A;
ET
B
: Endothelin type B; ER: Endoplasmic reticulum; ERK: Extracellular signal-
regulated kinase; FA: Filtered air; Fer-1: Ferrostatin-1; Foxp3: Forkhead box
transcription factor P3; FTL: Ferritin light chain; FTH1: Ferritin heavy chain;
GSH: Glutathione peroxidase; GSH-Px: Glutathione peroxidase; HDL: High-
density lipoprotein; HDL-C: High density lipoprotein-cholesterol; HDL-P: High-
density lipoprotein cholesterol particle matter; HOI: HDL oxidant index; Hs-
CRP: High sensitive C-reactive protein; HRP: High-risk plaque; HUVECs: Human
umbilical vein endothelial cells; IL: Interleukin; IAD: Inter-adventitial diameter;
IMT: Intima-media thickness; iNOS: Inducible nitric oxide synthase;
IQR: Interquartile; 7-KCh: 7-ketocholesterol; LDH: Lactate dehydrogenase;
LDL: Low-density lipoprotein; LDL-C: Low density lipoprotein-cholesterol;
LDPI: Laser Doppler perfusion imaging; LOX-1: Lectin-like oxidized low-
density lipoprotein receptor-1; LXR-α: Liver X receptor α; MAECs: Mouse aorta
endothelial cells; 3-MA: 3-Methyadenine; MAPK: Mitogen-activated protein
kinase; MCP: Monocyte chemoattractant protein; MDA: Malondialdehyde;
MMP: Matrix metalloproteinase; MMP: Mitochondrial membrane potential;
MRI: Magnetic resonance imaging; NAC: N-acetyl-L-cysteine; NF-κB: Nuclear
factor kappa-B; NO: Nitric oxide; NIST: National Institute of Standards and
Technology; 8-OHdG: 8-hydroxy-2’-deoxyguanosine; NLRP3: NOD-like
receptor protein 3; O
3
: Ozone; OC: Organic carbon; OR: Odds ratio; ox-
LDL: Oxidized low-density lipoprotein; PAH: Polycyclic aromatic hydrocarbon;
4-PBA: 4-phenylbutyrate; PCAECs: Premature coronary arterial endothelial
cells; PGES: Prostaglandin E synthase; PGE2: Prostaglandin E 2; PM
2.5
: Fine
particulate matter; PM
2.5abs
: Absorbance levels of PM
2.5
; PMA: Phorbol-
myristate-acetate; PLC: Phospholipase C; PKC: Protein kinase C; PNacc: Particle
number of accumulation mode particles; PP: Pilse pressure; PWV: Pulse wave
velocity; Rapa/Rap: Rapamycin; ROS: Reactive oxygen species; SA-β-
gal: Senescence associated-βgalactosidase; SBP: Systolic blood pressure;
SO
2
: Sulfur dioxide; SOD: Superoxide dismutase; sICAM-1: Soluble Intercellular
Adhesion Molecule-1; SR-BI: Scavenger receptor type B1; TAC: Thoracic aortic
calcium agatston score; T-AOC: Total antioxidant capacity; TC: Total
cholesterol; TF: Tissue factor; TFPI: Tissue factor pathway inhibitors;
TFRC: Transferrin receptor; TG: Triglycerides; TGF-β: Ttransforming growth
factor-β; TM: Thrombomodulin; TIMP3: Tissue inhibitor of metalloproteinase
3; TNF-α: Tumor necrosis factor α; TLR: Toll-like receptor; UFP: Ultrafine
particles; VCAM-1: Vascular cell adhesion molecule-1; VE: Vascular endothelial;
VEGF: Vascular endothelial growth factor; VEGFR2: Vascular endothelial
growth factor receptor 2; VOC: Volatile organic compounds; VSMCs: Vascular
smooth muscle cells; vWF: Von willebrand factor; WDE: Whole diesel exhaust;
WHO: World Health Organization; ZO-1: zonula occludens-1
Acknowledgments
Not applicable.
Liang et al. Particle and Fibre Toxicology (2020) 17:61 Page 18 of 24
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Authors’contributions
All authors contributed to the design, concept and grammar in this article.
Junchao Duan and Zhiwei Sun revised the manuscript. All authors read and
approved the final manuscript.
Funding
This work was supported by National Key Research and Development
Program of China (2017YFC0211600, 2017YFC0211602, 2017YFC0211606),
National Natural Science Foundation of China (91943301), Beijing Nova
Program (Z181100006218027) and Beijing Outstanding Talent Training
Program, Beijing Natural Science Foundation Program and Scientific Research
Key Program of Beijing Municipal Commission of Education
(KZ202110025040).
Availability of data and materials
Databases/repositories and materials is not applicable in this review.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declared they had no conflict of interest.
Author details
1
Department of Toxicology and Sanitary Chemistry, School of Public Health,
Capital Medical University, Beijing 100069, People’s Republic of China.
2
Beijing Key Laboratory of Environmental Toxicology, Capital Medical
University, Beijing 100069, People’s Republic of China.
Received: 17 May 2020 Accepted: 17 November 2020
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