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Links between atherosclerotic and periodontal disease
PII: S0014-4800(16)00007-1
DOI: doi: 10.1016/j.yexmp.2016.01.006
Reference: YEXMP 3897
Please cite this article as: Chistiakov, Dimitry A., Orekhov, Alexander N., Bobryshev,
Yuri V., Links between atherosclerotic and periodontal disease, Experimental and Molec-
ular Pathology (2016), doi: 10.1016/j.yexmp.2016.01.006
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Review Article
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Dimitry A. Chistiakov a, Alexander N. Orekhov b,c,d, Yuri V. Bobryshev b,e,f, *
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a
Department of Molecular Genetic Diagnostics and Cell Biology, Institute of Pediatrics, Research
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Center for Children's Health, 119991 Moscow, Russia;
b
Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences,
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Moscow 125315, Russia;
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Institute for Atherosclerosis, Skolkovo Innovative Center, Moscow 143025, Russia;
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Department of Biophysics, Biological Faculty, Moscow State University, Moscow 119991, Russia;
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e
Faculty of Medicine, School of Medical Sciences, University of New South Wales, Kensington,
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Correspondence to:
Dr Yuri V. Bobryshev
Faculty of Medicine
University of New South Wales
Sydney, NSW 2052
Australia
Tel/Fax: + 612 93851217
E-mail: y.bobryshev@unsw.edu.au
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ABSTRACT
Periodontal disease (PD) and cardiovascular disease (CVD) are highly prevalent in the modern
community. Both pathologies are chronic inflammatory disorders, which are influenced by multiple
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risk factors. In part, these factors such as age, smoking, and diabetes overlap between PD and CVD.
Epidemiological studies suggest that PD is strongly associated with increased CVD risk.
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Biochemical and physiological analyses involving in vitro experiments, animal models, and clinical
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studies provided evidence for the substantial impact of periodontal pathogens, their virulence
factors, and bacterial endotoxins on all general pathogenic CVD mechanisms such as endothelial
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dysfunction, systemic inflammation, oxidative stress, foam cell formation, lipid accumulation,
vascular remodeling, and atherothrombosis. Interventional studies showed moderate beneficial
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effects of PD treatment on reducing systemic inflammation and endothelial dysfunction. However,
no interventional studies were performed to assess whether periodontal therapy can primarily
prevent CVD. In summary, current data suggest for a strong contributory role of periodontal
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infection to CVD but cannot provide sufficient evidence for a role of PD as a cause for
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cardiovascular pathology.
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LPS, Inflammation
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1. Introduction
Teeth are surrounded by gingival tissue. Between the tooth and gingival tissue, a space
(termed gingival sulcus) can occur. The gingival sulcus is lined by sulcular epithelium that joins
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with the oral cavity epithelium at the top of the gingival margin. In the gingival sulcus, the
epithelium and crown enamel form unique surfaces colonized by oral bacteria. In this
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microenvironment, bacteria form a biofilm called dental plaque.
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Primary colonizers, which populate the gingival sulcus, involve streptococci (such as
Streptococcus oralis, S. mutans, and S. sanguis), Neisseria sp., etc. These anaerobic bacteria greatly
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decrease local availability of oxygen thereby providing an option for obligate anaerobes to populate
and grow in the gingival sulcus. In the dental plaque, primary colonizers provide substrates and
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form a background for attachment of secondary colonizers (that are predominantly anaerobic) such
as actinomycetes (Actinomyces odontolyticus and A. naeslundii), Fusobacterium nucleatum,
Veillonella sp., etc. (Rickard et al., 2003). Overall, the dental plaque microflora exceeds 500 species
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In the dental plaque, bacterial composition is influenced by many factors including supply
with oxygen, pH, diet, oral hygiene, and interactions between microbes.
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Above and below the gingival margin, bacterial composition significantly differs. In healthy
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smoking, altered immunity, and other harmful factors could induce gingivitis (i.e. inflammation of
gum tissue). Subgingival plaque could play a major role in the development of gingivitis.
In gingivitis, numbers of subgingival plaque microorganisms greatly increase along with the
enrichment of the subgingival plaque microflora with gram-negative obligate anaerobes (Moore et
al., 1987) including Porphyromonas gingivalis (Socransky et al., 1991), Aggregatibacter
actinomycetemcomitans (Zambon et al., 1983), Prevotella intermedia (Yang et al., 2014),
Prevotella melaninogenica (Mandell et al., 1992), Tannerella forsythensis (Yang et al. 2004),
Fusobacterium periodontium (Kobayashi et al., 2004), and Campylobacter rectus (Gmür et al.,
2004). All these bacteria and some other microbes are pathogens involved in gingivitis and
periodontitis.
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In the subgingival plaque, bacteria form complex relations between each other and host
cells. Plaque microbes are embedded into the extracellular matrix (ECM) of the sulcular epithelium
(Gibbons, 1989). Periodontopathogens such as P. gingivalis and A. actinomycetemcomitans invade
epithelial cells via the mechanism of endocytosis (Meyer et al., 1996). In the host cells, bacteria
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amplify and spread through intercellular protrusions to other cells (Andrian et al., 2006). The
bacterial invasion is accompanied by release of proinflammatory mediators that attract
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proinflammatory immune cells to the gingival sulcus (Jotwani et al., 2001). Periodontal pathogens
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exhibit marked adaptation capacity that supports survival within the invaded cells, neutralization of
immune cells, inactivation of anti-microbial factors, and induction of host mechanisms leading to
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tissue degradation (Amano, 2007).
The deepening of the gingival sulcus caused by dental plaque growth, local inflammation,
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and bacterially mediated destruction of the gingival fiber attachment leads to the formation of the
periodontal pocket. The periodontal pocket is a preferable site for accumulation of periodontal
pathogens where they aggravate inflammation of surrounding tissues and could stimulate
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progression of gingivitis to periodontal disease (PD) (Smalley, 1994). In PD, the connective tissue
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attachment is lacking and the dental plaque expands apically along the root tissue causing
progressive loss of the alveolar bone around the tooth and finally loss of the tooth itself. In
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periodontitis, the periodontal pocket releases gingival crevicular fluid (GCF), an inflammatory
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exudate containing cell debris, bacterial degradation products, inflammatory mediators, connective
tissue fragments, enzymes, and other proteins (Subrahmanyam and Sangeetha, 2003). Inflamed
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periodontal tissue is frequently or persistently bleeding providing an option for periodontal infection
to enter the bloodstream.
Indeed, oral pathogenic bacteria and their endotoxins could disseminate into the systemic
circulation via gingival injuries and affect distant organs (Hirschfeld and Kawai, 2015). Oral
commensals may represent a serious risk for individuals with predisposive cardiac alterations (heart
valve disease, pacemaker implantation, and so on) and cause infective endocarditis (Ito, 2006). First
evidence for positive association between the poor dental health and myocardial infarction (MI)
(Mattila et al., 1989) initiated a wave of interest to study possible relations between dental
infections and cardiovascular diseases (CVD) including atherosclerosis. Despite for heterogeneity
of the studies, overall results of epidemiological studies suggest for a modest but significant
association between periodontal infections and CVD that is independent on the effects of
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confounders (Kebschull et al., 2010). Experiments in animal models and in vitro studies found
potential molecular mechanisms linking PD and atherosclerosis.
2. Epidemiological studies
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Findings from the major epidemiologic studies involving thousands of individuals were
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comprehensively discussed in recent reviews (Kebschull et al., 2010; Lockhart et al., 2012). Several
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meta-analyses were performed and a positive association between PD and cardiovascular disease
(CVD) was reported. Blaizot et al. (2009) showed that PD patients have increased risk of
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developing CVD (odds ratio (OR), 2.35 (95% confidence interval (CI): 1.87; 2.96), p < 0.0001) and
relative risk (RR), 1.34 (95% CI: 1.27; 1.42), p < 0.0001). Sfyroeras et al. (2012) found association
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between PD and ischemic stroke reporting that PD subjects have 1.47-fold and 2.63-fold adjusted
risk to develop stroke in prospective and retrospective studies respectively. In a recent meta-
analysis, Orlandi et al. (2014) observed significant association of periodontitis with increased
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between PD and CVD (Hujoel et al., 2002). Current multivariate analyses include adjustments for
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several smoking-related variables such as smoking status, a quantity of pack-years, a time after
cessation, second-hand smoking, etc. (Nasry et al., 2006; Costa et al., 2013). Indeed, correction for
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when PD-CVD association was first reported. Indeed, this finding is not a false post hoc
observation.
Recently, in a large-scale retrospective cohort study, Chou et al., (2015) reported that
patients with treated severe periodontitis aged > 60 yrs have increased risk of long-term major
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adverse cardiovascular events compared with younger subjects (<60 yrs). The association remained
after adjustment for other potential CVD-related confounders such as gender, hyperlipidemia,
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hypertension, and diabetes. This finding compromises results of earlier studies for a stronger PD-
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CVD association in younger PD individuals. However, the history of smoking was not taken into
consideration in this study (due to data unavailability in the Taiwan National Health Insurance
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Database) that may seriously alter the value of observed associations.
A significant heterogeneity in methodology of definition of periodontitis could complicate
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explanation of observed associations between PD and CVD. In most observational studies, the
status of periodontitis was accessed radiographically (loss of alveolar bone) or clinically (tooth loss,
bleeding upon probing, depth of the periodontal pocket, rate of the fiber attachment loss). Beck and
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Offenbacher (2002) showed that attachment loss, pocket depth, and bleeding upon probing are
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individually associated with levels of circulating systemic inflammatory markers such as C-reactive
protein (CRP) and soluble intercellular adhesion molecule (sICAM), i.e. biomarkers of acute phase
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inflammation and vascular stress respectively. However, among these clinical approaches, bleeding
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assessment showed the best results for association with CRP while pocket depth was superior for
association with sICAM. Further studies confirmed correlation of bleeding on probing with levels
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of systemic inflammation markers such as CRP (Bokhari et al., 2014), interleukin (IL)-18, and C-X-
C motif chemokine ligand (CXCL)-16 (Schallhorn et al., 2010) in patients with coronary artery
disease (CAD).
Indeed, since association between periodontal markers and systemic inflammation markers
(Noack et al., 2001; Pejcic et al., 2011) was shown, a possible contribution of periodontitis to
chronic inflammatory disease such as atherosclerosis may consist in PD-dependent stimulation of
systemic (i.e. vascular inflammation).
In a meta-analysis, Mustapha et al. (2007) showed that elevated systemic bacterial exposure
(mainly assessed by serological measurements of antibody responses to periodontal microbes) is
associated with increased CAD risk (OR, 1.75 (95% CI: 1.32; 2.34), p < 0.001). However, the
utility of measurements of systemic antibody titers to assess the degree of pathogen exposure is
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limited since observed correlations between serum antibody to periodontal bacteria and clinical
periodontal conditions are species-specific (Dye et al., 2009) and increased antibody titers may
reflect activation of adaptive immunity against periodontal pathogens and PD severity. When
considering systemic antibodies levels as indicator of degree of infectious exposure, it is necessary
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to take into account smoking status and tooth loss since edentulous subjects and smokers exhibit
lower antibody responses than dentate individuals and never-smokers do (Vlachojannis et al.,
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2010). To date, no experimental studies were done to evaluate carefully whether combinations of
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clinical, bacterial, and antibody-based assessments may strengthen the accuracy of exposure
definitions and prognosis of CVD-associated outcomes.
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Regarding CVD-associated outcomes, PD showed a stronger association with ischemic
stroke than with coronary heart disease (CHD) (Hujoel et al., 2000; Dietrich et al., 2008; Jimenez et
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al., 2009). These findings were based on large-scale epidemiological data such as NHANES I and
Normative Aging Study (NAS). Watt et al. (2012) reported a correlation between tooth loss and
overall CVD mortality that was mainly driven by fatal cerebrovascular events. However, the
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mechanisms explaining why periodontitis exhibits a stronger risk factor for stroke than for CAD are
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unknown.
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3. Periodontal therapy
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The main goal of intervention studies is to evaluate whether treatment of periodontitis can
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bacteremia caused by periodontal procedures in almost a half (49.4%) of treated patients.
In 6-month post-treatment follow-up studies, an overall reduction in serum levels of
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systemic inflammatory markers including IL-6, TNF-α, and CRP was observed (S’Aiuto et al.,
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2004; Tonetti et al., 2007, Paraskevas et al., 2008; Marcaccini et al., 2009). Using an evaluation
scale of 19 inflammatory markers, Behle et al. (2009) showed the heterogeneity of systemic
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inflammatory responses after periodontal treatment, with reduction (or increase) in inflammatory
markers in 25-30% patients during 1-month post-treatment follow-up. A meta-analysis performed
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by Demmer et al. (2013) showed modest reductions in systemic CRP levels in the earliest post-
treatment time point (usually 1-3 months).
In regard to CVD risk factors, Nakajima et al. (2010) observed significant reduction in
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serum CRP and IL-6 only in the subgroup of periodontally treated subjects highly susceptible to
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increased CHD risk. Similarly, Correa et al. (2010) reported decrease in systemic inflammatory
markers in type 2 diabetic patients 3 months after non-surgical periodontal therapy. In summary,
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periodontal therapy seems to have short-term beneficial effects on systemic inflammation including
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patients at CVD risk. However, it is unclear whether treatment of periodontitis has a long-term
favorable effect on systemic inflammatory markers.
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antibiotics was shown to improve EDD (Seinost et al., 2005; Elter et al., 2006; Tonetti et al., 2007).
Overall, a recent meta-analysis showed beneficial effects of periodonthal therapy on endothelial
function in part through increasing FMD (Orlandi et al., 2014).
cIMT (a measurement of the thickness of carotid tunica media and tunica intima) is a
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surrogate marker of carotid atherosclerosis. cIMT monitoring is a valuable tool for detecting
atherosclerotic plaque and tracking regression or progression of atherogenesis. PD, especially in
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severe form, was shown to be associated with increased cIMT (Beck et al., 2001; Leivadaros et al.,
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2005; Cairo et al., 2008; Yu et al., 2014) suggesting for a predisposing role periodontitis in carotid
atherosclerosis. Tapashetti et al. (2014) showed correlation between CRP levels and cIMT in
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patients with chronic periodontitis indicating that PD-induced inflammation could contribute to
carotid atherosclerosis. In a meta-analysis, Orlandi et al. (2014) confirmed association between PD
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and increased cIMT (mean increase in c-IMT of 0.08 mm (95% CI: 0.07; 0.09)). PD therapy was
shown to significantly reduce c-IMT during 12-month post-treatment follow-up (Piconi et al., 2009;
Kapellas et al., 2014) but not pulse wave velocity (PWV) (Kapellas et al., 2014) suggesting that
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with higher atherosclerotic risk. In periodontitis patients, PWV was found to be significantly
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increased (Houcken et al., 2015). However, periodontal treatment of hypertensive PD patients did
not lead to reducing PWV 6 months after therapy (Houcken et al., 2015). In other study, Vidal et al.
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(2013) showed beneficial effects of periodontal therapy on arterial stiffness and other CVD-related
characteristics such as circulating inflammatory markers, blood pressure, and left ventricular mass
in 6-month follow-up of treated patients with refractory hypertension.
In the Periodontitis and Vascular Events (PAVE) study aimed to examine whether PD
treatment decreases CVD risk, no beneficial effects were achieved in the periodontally treated
patients with CVD history during a follow-up period of 6 to 25 months compared to those who used
community dental care, except for a trend in a less incidence of adverse events in treated subjects
(Beck et al., 2008). However, almost a half (48%) of patients randomized in the community care
group received preventive or periodontal care outside the study, a fact that could compromise the
validity of obtained results. Overall, systematic review of randomized trials performed to verify
whether periodontal therapy could prevent or manage CVD in individuals with chronic PD failed to
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reveal favorable effect of non-surgical PD treatment due to the low quality evidence (Li et al., 2014;
Henschel and Keenan 2015). In fact, the only a single randomized controlled trial (i.e. the PAVE
study) was performed to date.
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4. Periodontal pathogens in animal models of atherosclerosis
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Apolipoprotein E (ApoE)- and low density lipoprotein (LDLR)-deficient mice are
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established rodent models of human atherosclerosis. Both models were challenged with periodontal
pathogens or their endotoxins/antigens in order to study potential molecular mechanisms linking
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periodontal infection and atherosclerosis (Table 1). In overall, oral infection of atherosclerotic mice
with single or several periodontal bacteria led to advanced disease accompanied with increased
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plaque progression, enhanced macrophage infiltration, elevated levels of inflammatory markers,
lipid accumulation in the arterial wall, foam cell formation, and advances in other proatherogenic
signs (Kebschull et al., 2010).
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In mice, invasion patterns were different between periodontal pathogens. P. gingivalis DNA
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was detected in the aorta, liver, and heart (Li et al., 2002). Furthermore, in ApoE-deficient mice, P.
gingivalis was able to access brain and induce complement activation and brain inflammation while
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other periodontal pathogens (F. nucleatum, Treponema denticola, and T. forsythia) did not (Poole et
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effects of periodontal endotoxemia (Wiesner et al., 2010). Toll-like receptors (TLRs), i.e. innate
immune receptors recognizing various pathogen-associated molecular patterns (PAMPs) play a
primary role in mediating effects of periodontal bacterial antigens and virulence factors (Bainbridge
and Darveau, 2001; Hajishengallis et al., 2002).
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Fimbrillin (FimA), a structural component of fimbriae (attachment pilli), plays a central role
in P. gingivalis colonization and virulence (Yoshimura et al., 2009). FimA-deficient P. gingivalis
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mutants were unable to up-regulate TLR2 and TLR4 and promote atherosclerosis in ApoE-deficient
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mice (Gibson et al., 2004). Both TLRs are not involved in binding bacterial fimbriae. Other pattern-
recognition receptors (PRRs) namely CD14 and CD11b/CD18 interact with fimbriae but TLR2 and
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TLR4 mediate cell activation in response to fimbriae (Hajishengallis et al., 2004). In vascular
endothelial cells (ECs), P. gingivalis FimA is involved in TLR2- and TLR4-dependent up-
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regulation of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), vascular cell
adhesion molecule-1 (VCAM-1), E-selectin, and P-selectin (Khlgatian et al., 2002). In monocytes,
TLR2 mediates monocyte adhesion to activated ECs in response to P. gingivalis P. gingivalis and
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monocytes.
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protein (OMP) (Koizumi et al., 2008). OMPs are expressed on the surface of gram-positive bacteria
and are responsible for survival of engulfed bacteria in macrophages and cell invasion.
Immunization of ApoE-deficient mice with P. gingivalis 40-kDa OMP induces humoral immune
response and production of 40-kDa OMP-specific antibodies (IgG1, IgG2b, and IgA) (Koizumi et
al., 2008) that inhibit bacterial coaggregation and biofilm formation and hence reduce P. gingivalis
pathogenicity and atherogenicity upon injection (Namikoshi et al., 2003).
Madan et al. (2007) attempted to model effects of periodontal treatment on atherosclerosis
and systemic inflammation. Since mechanical dental therapy is not acceptable in mice, the authors
used systemic administration of doxycycline (an antibiotic). In ApoE heterozygotic mice, treatment
with doxycycline had anti-atherogenic effect by reducing both P. gingivalis-mediated atherogenesis
and inflammation (Madan et al., 2007). However, these findings are not applicable in humans where
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periodontitis is mediated by dental plaque, i.e. by biofilm that greatly increases bacterial resistance
to antibiotics (Lewis, 2008). Indeed, this can explain inefficacy of systemic therapy with antibiotics
in the secondary prevention of cardiac events (Grayston et al., 2005; Stassen et al., 2008; Almalki
and Guo 2014). In mice, Madan et al. (2007) used repeated injections of P. gingivalis that did not
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lead to the formation of a stable biofilm. Hence, non-aggregated P. gingivalis bacteria are more
sensitive to an antibiotic.
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In summary, elaborating of experimental models of atherosclerosis resulted in obtaining
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useful data about pathogenic mechanisms linking periodonatal infections and atherogenesis. For
example, Arg-specific gingipain, one of two gingipain endoproteases released by P. gingivalis, was
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shown to specifically cleave apoB-100, a key protein moiety in LDL (Miyakawa et al., 2004).
Pathogen-mediated ApoB-100 degradation results in LDL aggregation, rising LDL levels,
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generation of foam cells, and enhanced lipid deposits in the arterial wall of ApoE-deficient mice
(Hashimoto et al., 2006). Protein convertase subtilisin/kexin type 9 (PCSK9) is activated in PD
patients (Miyazawa et al., 2012a). In mice, Miyazawa et al. (2012b) showed that P. gingivalis
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transcription factor 2 (Srebf2)-dependent fashion. PCSK9 binds to LDLR and enhances lysosomal
degradation of the receptor (Sasaki et al., 2014). Decrease in LDLR density on the surface of
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hepatocytes leads to elevated plasma LDL cholesterol and induces hypercholesterolemia in mice
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(Miyazawa et al., 2012b). These two examples explain how P. gingivalis invasion could contribute
to atherogenesis by altering lipid metabolism and homeostasis.
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Findings obtained in animal atherosclerotic models may have limited relevance to humans.
Investigators usually challenged hypercholesteroemic mice with repeated administration of
periodontal monoinfections that are unlikely to form stable biofilms while in humans PD is
mediated by bacterial community (i.e. dental plaque) composed of several or multiple periodontal
pathogenic species. However, using animal models of atherosclerosis remains to be very helpful for
studying pathogenic mechanisms of atherogenesis.
Bacteremia and endotoxemia are two main mechanisms by which PD pathogens may
directly influence atherogenesis and initiate pathological events linking PD and atherosclerosis.
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Bacteremia refers to the presence of bacteria in the blood while endotoxemia means the presence of
endotoxins in the circulation.
In oral cavity, enter of periodontal bacteria to the bloodstream commonly occurs after dental
treatments and may happen during chewing food (Geerts et al., 2002) and after dental hygiene
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procedures such as tooth brushing and dental flossing (Crasta et al., 2009; Zhang et al., 2013),
especially in patients with gingivitis or periodontitis. In PD, bacteremia happens due to the
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interruption of oral epithelium in the periodontal pocket and/or contacts between the subgingival
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plaque and adjacent microvessels (Nanci and Bosshardt, 2006). The extent of bacterial blood
dissemination depends on the magnitude of tissue trauma, bacterial density in the dental plaque, and
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severity of local inflammation (Wilson et al., 2007). The gingival sulcus progressing to the
periodontal pocket is the major source and portal for entry of periodontal bacteria to the circulation
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(Strom et al., 1998).
Around 300 distinct oral bacterial species were found in blood samples after single-tooth
extraction and dental brushing (Bahrani –Mouqeot et al., 2008; Lockhart et al., 2008). More
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Micrococcus micros and species Streptococcus and Actinomyces (Horliana et al., 2014). In the
blood, oral bacteria circulate freely or within cell autophagosomes. Through the circulatory system,
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periodontal bacteria can reach distant organs. Bacteria could attach to and invade various vascular
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cells including arterial ECs and arterial smooth muscle cells (SMCs) (Dorn et al., 1999; Dorn et al.,
2001).
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samples, Nakano et al. (2006) found presence of Streptococcus mutans DNA, a caries causative
agent, while prevalence of other bacteria including periodontal pathogens was significantly less.
This finding may indicate an option for teeth decay-causing bacteria to use disrupted epithelium as
a gate for extra-oral dissemination. Due to significant inconsistency of available data, it is difficult
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to conclude whether periodontal pathogens can cause atherosclerosis in humans.
Current diagnostic approaches used for detection of bacteria in the plaque were
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comprehensively criticized due to methodological limitations (Ieven and Hoymans 2005).
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Periodontal pathogens found in the atheroma were proposed to not be directly involved in the
plaque formation. The local infection burden, which could promote CVD pathogenesis through
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inflammatory mechanisms, was suggested to serve as a more reliable cardiovascular risk marker
(Zhu et al., 2000; Georges et al., 2003).
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Endotoxins released by periodontal bacteria can induce and mediate distant inflammation
through the circulation. In severe periodontitis, serum levels of LPS due to the overgrowth of
periodontal gram-negative microorganisms are increased (Pussinen et al., 2004). In healthy patients,
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circulating LPS is mainly associated with high density lipoprotein (HDL). However, in chronic PD,
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shift of LPS toward less dense and proatherogenic lipoprotein such as LDL and very light density
lipoprotein (VLDL) occurs (Rufail et al., 2007; Kallio et al., 2008). VLDL- and LDL-associated
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proinflammatory messengers such as IL-6, macrophage chemotactic protein-1 (MCP-1), and TNF-α
(Kallio et al., 2013). In induction of proinflammatory activation of macrophages, low levels of LPS
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were shown to act synergistically with minimally oxidized LDL (oxLDL) through derepression of
transcription factor AP-1 and activation of nuclear factor (NF)-κB that drive expression of
proinflammatory genes (Wiesner et al., 2010).
Along with the induction of the proinflammatory phenotype, LPS from periodontal microbes
promote accumulation of LDL cholesterol in macrophages and generation of foam cells through
inhibition of expression of scavenger receptor B1 (SRB1) (HDL-binding receptor) and ATP-
binding cassette transporter 1 (ABCA1) responsible for reverse cholesterol transport (Lakio et al.,
2006). Periodontitis also reduces the anti-atherogenic potential of HDL via decreasing HDL
capacity to mediate cholesterol efflux from macrophages (Pussinen et al., 2004) and altering
expression and activity of proteins involved in lipoprotein metabolism such as phospholipid transfer
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protein (PLTP), lecithin-cholesterol acyltransferase (LCAT), and cholesterol ester transfer protein
(CETP) (Pussinen et al., 2001).
Indeed, LPS from periodontal pathogens can promote atherogenesis via multiple
mechanisms that involve serum lipid redistribution towards formation of proatherogenic lipid
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profile and cooperation with LDL, VLDL, and oxLDL in induction of vascular inflammation and
lipid accumulation in macrophages.
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Bacterial products of periodontal pathogens serve as antigens that induce humoral immunity
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and production of antibodies specific to periodontal bacteria. Bacterial proteins could share
molecular homology with host proteins. This in turn may initiate cross-reactivity between pathogen-
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specific antibodies and host proteins through the mechanism of molecular mimicry.
6. Molecular mimicry
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This phenomenon results from the sequence similarities between foreign antigens and self-
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antigens that may induce cross-activation of autoreactive T- and B-lymphocytes by foreign antigens
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induced by many inflammatory and non-inflammatory stimuli including exposure to LPS (Wick et
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al., 2008). Mammalian HSP60 share significant homology with bacterial chaperonin GroEL
presented in P. gingivalis and other periodontal pathogens. In PD patients, GroEL-specific humoral
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data argue for a role of HSP60/GroEL identity as a link between periodontitis and atherosclerosis.
Moreover, the anti-inflammatory peptide 19 has a value as a putative therapeutic tool for treatment
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of CVD and PD.
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As mentioned above, P. gingivalis produce two endopeptidases, Arg-specific and Lys-
specific gingipain. These proteases play an important role in bacterial adhesion, colonization,
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defense, and invasion through interaction with ECM proteins of host cells, degradation of ECM and
surface receptors, and proteolytic inactivation of cytokines and antibodies (O-Brien-Simpson et al.,
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2003). P. gingivalis gingipain was found to share homology with LDL modified with
malondyaldehide (MDA-LDL) and could be recognized by MDA-LDL-specific antibodies
(Turunen et al., 2012). Immunization with MDA-LDL of LDLR-deficient mice challenged with P.
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gingivalis had atheroprotective effect by reducing lipid depositions in the arterial wall and inducing
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the anti-atherogenic humoral immune response (Turunen et al., 2015). MDA-LDL and other
modified LDL are highly immunogenic, pro-inflammatory and atherogenic (Rafieian-Kopaei et al.,
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2014). Indeed, natural IgM directed against P. gingivalis infection are able to bind and neutralize
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In the bloodstream, periodontal bacteria may interact with various vascular and circulating
immune and non-immune cells exerting different effects on each cell population (Fig. 1). Most of
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data related to the interactions between periodontal pathogens and host cells were obtained from in
vitro experiments in which cultured cells were exposed to bacteria and their products. However,
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many important findings were done in animal models and affected patients. P. gingivalis was used
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as a model organism of periodontal infection.
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7.1. Endothelial dysfunction
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In bacteremia, periodontal pathogens interact with vascular ECs in order to escape from fast
clearance by immune cells. One of the evading ways is the invasion of ECs by pathogenic bacteria
(Progulske-Fox et al., 1999). Endothelial invasion by P. gingivalis is critically mediated by
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hemagglutinin A (HagA) (Bélanger et al., 2012), hemagglutinin B (HagB) (Song et al., 2005), and
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various adhesion molecules on the surface of vascular ECs and production of inflammatory
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messengers including IL-6, MCP-1, IL-8, and cyclooxygenase-2 (COX-2) (Nassar et al., 2002;
Chou et al., 2005; Takanashi et al., 2006; Ho et al., 2009). FimA also stimulates expression of
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TLR4 that in turn sensitizes ECs to P. gingivalis LPS (Yumoto et al., 2005). Indeed, LPS and FimA
could cooperate in proinflammatory activation of arterial endothelium by P. gingivalis.
Periodontal bacteria induce proinflammatory activation of ECs with different capacity. For
example, P. gingivalis is a robust inducer of endothelial MCP-1 production while T. forsythia
modestly activates MCP-1 expression and T. denticola has no visible effects (Niu and Kolattukudy
2009). In invaded cells, P. gingivalis and A. actinomycetemcomitans influence distinctive pathways.
A. actinomycetemcomitans-associated network is related to EC function whereas P. gingivalis
mainly affects MAPK-dependent pathways (Lv et al., 2015). Compared with P. gingivalis, A.
actinomycetemcomitans (and its leukotoxin) up-regulate expression of a less number of adhesion
molecules (i.e. ICAM-1, VCAM-1, and P-selectin) and do not activate NF-κB in ECs (Assinger et
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al., 2011; Dietmann et al., 2013). Indeed, each periodontal bacterium utilizes unique mechanisms of
host-pathogen interactions.
Up-regulation of endothelial expression of adhesion and chemoattractant molecules by
periodontal bacteria stimulates attachment of monocytes and other leukocytes on the surface of ECs
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(Hajishengallis et al., 2006; Roth et al., 2007b; Hashizume et al., 2011). Recruitment of monocytes
on the endothelial surface is the important event in early atherosclerosis that precedes their
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transendothelial migration to the arterial intima and differentiation to macrophages. P. gingivalis
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LPS was shown to mediate adhesion of monocytes via TLR2-dependent mechanism (Erridge et al.,
2007; Nakamura et al., 2008). In ECs, TLR2 activation leads to the adhesion and transmigration of
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monocytes associated with stimulation of Rac1 signaling and up-regulation of adhesion molecules
ICAM-1, CD11b, and CD18 (Harokopakis et al., 2006).
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P. gingivalis is able to increase vascular permeability through gingipain-dependent
mechanism. Gingipains cleave platelet endothelial cell adhesion molecule 1 (PECAM-1 or CD31)
that leads to the progressive gap formation between adjacent ECs (Yun et al., 2005). In ECs, P.
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of IL-8, a key inducer of vascular permeability (Kim et al., 2013). LPS and gingipains are released
from outer membrane vesicles (OMVs).
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fimbriae (Mantri et al., 2015). OMVs is a major virulence P. gingivalis factor (Bartruff et al., 2005).
OMVs could be internalized by recipient cells with 2-3-fold higher efficiency compared with
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bacterial cells. After 1h of exposure, 70-90% of cultured HUVECs had vesicles while 20-50% of
the host cells had internalized P. gingivalis cells (Ho et al., 2015).
Gingipains released from OMVs facilitate endothelial P. gingivalis attachment (Nassar et
al., 2002) and sensitize ECs to P. gingivalis LPS and to the pathogen itself by activation of release
of Weibel-Palade bodies (a store of vasoactive substances) (Inomata et al., 2007). Protease-
activated receptors (PARs) mediate cellular effects of gingipains. Through PAR activation,
gingipains cooperate in induction of IL-8 and MPC-1 production by ECs (Nassar et al., 2002).
OMVs were shown to inhibit endothelial nitric oxide (NO) synthase (eNOS), a key producer of NO
that plays a central role in the regulation of a proper endothelial function (Jia et al., 2015). P.
gingivalis-derived OMVs display anti-angiogenic and inhibitory effects on ECs via suppressing
their growth and proliferation and inducing apoptosis (Bartruff et al., 2005). Apoptotic properties of
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OMVs are mediated by gingipains that cleave adhesion molecules on the endothelial surface and
induce EC detachment (Baba et al., 2002; Sheets et al., 2005; Sheets et al., 2005; Roth et al.,
2007a). These findings suggest that P. gingivalis OMVs is the best offensive weapon supporting
pathogen survival, invasion, and P. gingivalis-induced endothelial dysfunction (Ho et al., 2015).
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EC apoptosis is a hallmark of atherosclerosis-related endothelial dysfunction. Endothelial
apoptosis persists during the atherosclerosis progression leading to EC detachment and denudation
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of the arterial wall. Endothelial dysfunction is the earliest vascular manifestation of atherosclerosis
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associated with other traditional CVD risk factors (Widlansky et al., 2003). In patients without
clinically manifected atherosclerosis, systemic endothelial dysfunction is associated with increased
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risk of adverse cardiac events (Heitzer et al., 2005; de Berrazueta et al., 2010).
At present, endothelial dysfunction is assessed with help of the digital pulse amplitude
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tonometry and ultrasonic evaluation of the brachial artery after flow-mediated vasodilation (FMD)
or nitroglycerin administration (Hamburg and Benjamin 2009; Onkelinx et al., 2012). In patients
with advanced PD, FMD was significantly reduced compared to the controls (Amar et al., 2003;
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Seinost et al., 2005). Mercanoglu et al. (2004) observed significant decrease in both endothelium-
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significant improvement in endothelial finction was observed (Mercanoglu et al., 2004; Higashi et
al., 2008).
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thickening (Chistiakov et al., 2015). In the neointima, migrated SMCs usually produce ECM to
form a fibrous cap that covers the necrotic plaque core (Lacolley et al., 2012).
The involvement of periodontal pathogens such as P. gingivalis in the neointimal
hyperplasia was shown in mice and humans. In a murine model of aortic hyperplasia induced by EC
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injury, intravenous injection of P. gingivalis led to dramatic increase in intimal hyperplasia
associated with overexpression of S100 Ca2+-binding protein A9 (S100A9) and embryonic isoform
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of myosin heavy chain (SMemb), a marker of SMC proliferation (Hokamura et al., 2010). Inaba et
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al. (2009) showed activation of S100A9 expression and phenotypic changes in human aortic SMCs
exposed to supernatant of plasma incubated with P. gingivalis. This indicates that soluble factors
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released by bacteria can induce SMC hyperplasia. Similarly, up-regulation of S100A9 and SMemb
was observed in aortic aneurisms of PD patients (Hokamura et al., 2010; Nakano et al., 2011)
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suggesting on the involvement of P. gingivalis in intimal hyperplasia.
In vitro experiments involving cultured arterial SMCs showed the ability of P. gingivalis
invade, survive, and transmit between the cells (Dorn et al., 1999; Dorn et al., 2002; Li et al., 2008).
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In infected cells, bacteria could alter expression of multiple genes. In human aortic SMCs invaded
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with P. gingivalis, Znang et al. (2013) observed changes in expression of a total of 982 genes in part
regulated by transforming growth factor (TGF)-β and Notch pathways, i.e. signaling mechanisms
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involved in cell proliferation, growth, and hypertrophy. Gingipains released by P. gingivalis were
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factor regulates angiogenesis through inhibiting antigiopoietin-1 and its receptor Tie-2 and
promoting migration of SMCs (Felcht et al., 2012). The ability of P. gingivalis to modulate balance
between these two angiogenic factors may be important in the context of intraplaque
neovascularization during pathological vascular wall remodeling.
Isolated rat coronary arteries exposed to LPS from P. gingivalis exhibited greater
contraction in response to endothelin-1 (Ghorbani et al., 2010). Bacterial LPS was shown to up-
regulate expression of the endothelin B receptor in SMCs that in turn sensitizes arteries to
endothelin-1-mediated vasoconstriction. In summary, P. gingivalis display opposite effects on
vascular cells. While inhibiting function, proliferation, and migration and inducing apoptosis of
ECs, this pathogen and its products support proliferation, growth, and motility of vascular SMCs,
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the evidence about a role of P. gingivalis in promoting atherogenic vascular remodeling (Hokamura
and Umemura 2010).
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Transendothelial migration of monocytes leads to the accumulation of macrophages in the
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arterial intima. In the intima, macrophages ingest lipids and transform to foam cells due to inability
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to efficiently utilize and pass away engulfed lipids. Foam cells are the main contributors of
lipid/necrotic core formation due to the death and degradation within the plaque (Hilgendorf et al.,
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2015). Periodontal pathogens such as P. gingivalis and their products (LPS, etc.) positively
contribute to all stages of monocyte fate in atherosclerosis supporting monocyte recruitment on the
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endothelial surface, intimal infiltration, differentiation to proinflammatory macrophages, and
transformation to foam cells (Roth et al., 2007b, Giacona et al., 2004; Uehara et al., 2008; Pollreisz
et al., 2010). P. gingivalis bacteria were shown to invade and survive in monocytes and
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macrophages, a phenomenon that could contribute to the transmission of the bacteria from the site
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of periodontal infection to other inflamed sites (Jayaprakash et al., 2014). Except for P. gingivalis,
the most studied periodontal pathogen, other periodontal bacteria such as T. forsythia (Lee et al.,
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2014) and A. actinomycetemcomitans (Lakio et al., 2006) were able to induce generation of foam
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cells.
Normally, macrophages could efficiently control serum lipoprotein and cholesterol
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homeostasis by well-regulated taking up and releasing lipids to the bloodstream (Graham 2015).
Periodontal pathogens and their endotoxins can disturb lipid metabolism in macrophages. In
patients with chronic PD, P. gingivalis LPS is mainly associated with proatherogenic LDL (Kallio
et al., 2008). LPS-LDL assemblies efficiently stimulate LDL-dependent proinflammatory activation
(Kallio et al., 2013) and increase uptake of LDL cholesterol by macrophages (Qi et al., 2003;
Miyakawa et al., 2004). LPS down-regulate expression of liver X receptors (LXR), which are the
key regulators of lipid catabolism in macrophages, along with suppressing ABCA1 and SRB1
(Lakio et al., 2006). In macrophages, P. gingivalis-derived LPS up-regulate CD36, a scavenger
receptor for LDL and oxLDL (Li et al., 2013; Brown et al., 2015). As a consequence, LDL
cholesterol and oxLDL accumulate in macrophages since both lipid catabolism and efflux are
suppressed by LPS.
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P. gingivalis and its vesicles not only stimulate LDL binding to macrophages but also
induce macrophages to modify native LDL that in turn increases LDL atherogenicity (Bolton et al.,
1994; Niu et al., 2000). LDL from blood exposed to P. gingivalis exhibited increased protein
oxidation and generation of two apoB-100 N-terminal fragments (likely due to the proteolitic
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activity of gingipains) (Bengtsson et al., 2008). Treatement of oxLDL-stimulated macrophages and
foam cells with P. gingivalis-derived LPS led to the stimulation of NF-κB pathway and up-
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regulation of proinflammatory cytokines IL-1β and IL-12 (Lei et al., 2011). Similarly, Groeneweg
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et al. (2006) reported that prior exposure to oxLDL enhanced proinflammatory effects of LPS on
macrophages by activating production of TNF-α, IL-6, and IL-12 whereas expression of anti-
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inflammatory IL-10 was decreased. Therefore, P. gingivalis LPS and oxLDL may act
synergistically in induction/stimulation of proinflammatory phenotype in macrophages and foam
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cells.
Oxidative stress occurs due to the excessive production of reactive oxygen species (ROS)
that cannot be fully scavenged and detoxified by antioxidant defenses. Oxidative stress leads to
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cytotoxicity. Production of peroxides and free radicals causes damage (frequently irreversible) of
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biomolecules such as proteins, nucleic acids, and lipids and inactivation of enzymes. Some ROS act
as cellular messengers in redox signaling. Indeed, oxidative stress could impair cell signaling (Siti
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et al., 2015, Perotta and Aquila 2015). Oxidative stress plays an important role in atherogenesis,
particularly by enhancing the oxidative modification of LDL (Peluso et al., 2012). ROS-mediated
formation of oxLDL is a prerequisite for cholesterol uptake by macrophages and the generation of
foam cells (Itabe 2009).
Periodontal pathogens could contribute to atherosclerosis-related oxidative stress through
promoting oxLDL formation (Kurita-Ochiai and Yamamoto 2014). In ApoEshl mice, infection with
A. actinomycetemcomitans led to elevated oxidative stress associated with lipid peroxidation,
increase in levels of oxidative stress markers (4-hydroxynoneal and 8-oxo-2′-deoxyguanosine), and
activation of phospholipase A2, myeloperoxidase and NADPH oxidase in the aorta (Jia et al.,
2013). P. gingivalis was shown to stimulate LDL oxidation in ApoE-deficient mice (Hashimoto et
al., 2006; Bengtsson et al., 2006).
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Indeed, PD patients display advanced lipid oxidation in the gingival crevicular fluid, blood, and
saliva (Akalin et al., 2007; Wei et al., 2010), and peroxidation level correlates with the severity of
periodontitis (Bastos et al., 2012).
Induction of the respiratory (or oxidative) burst could also contribute to oxidative stress. The
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respiratory burst is a host defense mechanism that typically occurs in immune cells such as
neutrophils, monocytes, and macrophages (called ‘professional phagocytes’) and refers to the fast
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ROS release upon contact with invaded microorganisms. In the respiratory burst, NADPH oxidases
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(NOXs) and myeloperoxidase are the major contributors to ROS production. NOXs are abundantly
present in phagocytic immune cells such as neutrophils, monocytes, and macrophages. These
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enzymes are needed to produce the oxidative burst in order to kill phagocytized microbes (Cross
and Segal 2004). MA
In PD, bacteremia induces the respiratory burst in phagocytes that is a normal reaction to
microbial invasion. Upon contact with neutrophils, P. gingivalis bacteria were shown to induce IL-8
and ROS production by neutrophils (Jayaprakash et al., 2015). Indeed, pathogen-induced
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respiratory burst may increase neutrophil-mediated oxidative damage of the surrounding tissue.
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Ramírez et al. (2014) observed increased serum levels of myeloperoxidase in subjects with
untreated chronic periodontitis suggesting for neutrophil activation. In GCF of PD patients taken
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from periodontitis sites, significantly higher levels of myeloperoxidase, lactoferrin, and glutathione
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peroxidase were detected compared with non-diseased sites indicating the local redox imbalance
and presence of oxidative stress (Wei et al., 2004). Rangé et al. (2014) reported potential
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As mentioned above, periodontal pathogens are able to induce proinflammatory activation of ECs.
Inflammatory activation of ECs may lead to increase in NOX activity (Kuramitsu et al., 2001).
Antioxidant treatment of ECs exposed to P. gingivalis and inhibition of NOX resulted in significant
reduction of endothelial MCP-1 production (Choi et al., 2015) thereby limiting monocyte
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transmigration to the arterial intima.
Generally, periodontal pathogens are anaerobic microorganisms. However, in the presence
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of hemin or within the dental plaque, peridontal anaerobes are able to tolerate increased levels of
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oxygen (Diaz et al., 2002; Diaz and Rogers 2004). Hemin and iron are essential for P. gingivalis
viability. Iron is required for P. gingivalis growth. Iron could be acquiesced from transferrin with
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help of gingipains that degrade this protein (Brochu et al., 2001). Gingipain-mediated degradation
of ferritin is accompanied with generation of toxic hydroxyl radicals (Goulet et al., 2004).
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Hemin is needed for synthesis of the cytochrome b subunit of P. gingivalis fumarate
reductase, a key generator of metabolic energy for this pathogen. Due to periodontal bleeding, red
blood cells can extravasate to the GCF where they release hemoglobin. P. gingivalis could extract
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hemin from hemoglobin through gingipain-mediated mechanisms (Lewis 2010). Gingipains have
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hemagglutinin domains capable to capture hemin from hemoglobin in cooperation with surface
hemagglutinins (De Carlo et al., 1999). Hemin is then stored on the surface of P. gingivalis cells in
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the form of μ-oxo-heme protecting bacteria against peroxide stress and phagocyte-induced oxidative
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burst (Smalley et al., 1998). In fact, periodontal pathogens such as P. gingivalis could colonize
hemorrhagic areas of unstable lesions adjacent to the necrotic core. These regions are hypoxic and
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enriched with deposits of iron and hemin essential for P. gingivalis life (Chiu 1999). Findings
recently obtained by Rangé et al. (2014) suggest for a potential contribution of periodontal bacteria
and their endotoxins to intraplaque hemorrhages and plaque destabilization.
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degradation is directed by matrix metalloproteinases (MMPs) that are produced by inflammatory
cells (mainly by macrophages) resided in or in the vicinity to the cap. P. gingivalis itself is able to
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degrade collagenous ECM in a gingipain-dependent manner, a common event that occurs during
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destruction of the periodontal connective tissue in PD (Baba et al., 2001; Al-Shibani and Windsor
2008). Periodontlal bacteria such as P. gingivalis, P. intermedia, and A. actinomycetemcomitans
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were shown to up-regulate production and matrix-degrading activity of various MMPs in different
cell types including ECs, monocytes, macrophages, and fibroblasts (Ding et al., 1995; Zhou and
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Windsor 2006; Madan et al., 2007; Tuomainen et al., 2008; Guan et al., 2008; Guan et al., 2009;
Zhou et al., 2012). LPS released by P. gingivalis was shown to act as a potent inducer of MMPs in
macrophages and fibroblasts (Kuo et al., 2012; Santos et al., 2013)
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Sato et al. (2009) found that exposure of fibroblasts to ultrasound-generated P. gingivalis bacterial
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periodontal bacteria and their products against ECs, fibroblasts, and other cells also contributes to
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lesion instability.
In a murine model of MI-induced cardiac injury, DeLeon-Pennell et al. (2013) showed that
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deleterious effects on heart function. This explains a strong association between PD and increased
post-MI mortality.
7.6. Atherothrombosis
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Thrombosis is a normal physiological process in response to vascular injury required for
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preventing blood loss and maintaining vascular integrity. In atherosclerosis, thrombogenic
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mechanism plays a pathophysiological role. Atherothrombosis is induced in diseased arterial
regions especially in disrupted plaques. Large thrombi greatly decrease blood flow causing tissue
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hypoxia due to oxygen deprivation. Thromboembolic events are caused by freely circulating
thrombi and may lead to anoxia (i.e. complete prevention of oxygen supply) and infarction (i.e.
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tissue death) (Furie and Furie, 2008).
Normal arterial endothelium exhibits anti-coagulant and anti-adhesion properties.
Periodontal pathogens such as P. gingivalis could induce procoagulant properties in ECs through
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Thrombomodulin (also known as CD141) resides on the plasma membrane of ECs and converts
thrombin from a procoagulant enzyme to an anti-coagulant enzyme. Due to the lack of
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thrombomodulin activity, thrombin can bind to plateles and induce their aggregation and release of
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serotonin (Esmon et al., 1983). Dental plaque inhabitans such as P. gingivalis and S. sanguis
express on the surface the platelet aggregation-associated protein (PAAP) that stimulate platelet
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without CAD and an inverse correlation between the salivary TF activity and the Community
Periodontal Index Treatment Needs (CPITN) scores. Indeed, this may suggest for a potential utility
of salivary TF as a marker of periodontitis and CAD. However, this finding should be
independently reevaluated in a larger group of patients because Emekli-Alturfan et al. (2011)
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measured TF activity only in 26 subjects affected with CAD + PD and in 26 cases of periodontitis.
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8. Conclusion
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Overall, epidemiological, interventional and functional studies show a significant
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association between peridontitis and CVD. Peridontal bacteria and their products could be involved
in all stages of atherogenesis. Furthermore, in vitro, animal, and clinical studies showed that
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periodontal pathogens positively influence all major proatherogenic mechanisms and hence
periodontal infection could play a contributory role in atherosclerotic pathogenesis. Observational
studies indicate that periodontal infection could increase CVD risk independently of other
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confounding factors. However, these observations cannot provide strong evidence that dental
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the independent role of periodontitis as a risk CVD factor was highlighted. Moderate evidence in
favor of plausible effects of periodontal therapy on the improvement of clinical and surrogate
markers of endothelial dysfunction and decrease in systemic inflammation was stated (Tonetti et al.,
2013). However, no beneficial effect of the periodontal treatment on the lipid profile was observed.
To date, limited evidence on improving procoagulant status, blood pressure, and subclinical
atherosclerosis after PD treatment was provided (Tonetti et al., 2013).
No periodontal interventional studies on primary CVD prevention were conducted. A single
interventional trial on secondary CVD prevention was done but had serious limitations to make
reasonable conclusions. Indeed, well-constructed interventional studies involving large numbers of
subjects and long-term follow-up should be performed to evaluate the contribution of PD therapy on
prevention of well-defined clinical CVD outcomes.
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The authors declare that the research was conducted in the absence of any commercial or financial
relationships that could be construed as a potential conflict of interest.
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Acknowledgements
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This work was supported by the Russian Science Foundation (grant #14-15-00112), Russian
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Federation.
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Legend to Figure
Fig. 1. Proatherogenic and proinflammatory effects of periodontal pathogens and their products on
host vascular and blood-borne cells. Periodontitis progression leads to the destruction of
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surrounding gingival tissues and microvessels that opens a portal for dissiminating periodontal
bacteria (bacteremia) and their endotoxins (endotoxemia) in the circulation and option to influence
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atherogenesis.
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Cardiol. 2000;85(2):140-6.
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Table 1. Effects of challenge of murine atherosclerosis models with periodontal pathogens and
their products
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deficient epitopes of P. gingivalis gingipain. (2012)
Immunization with P. gingivalis induced IgM,
response to MDA-LDL, and decreased aortic
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lipid accumulation
LDLR- P. gingivalis Immunization of P. gingivalis-challenged Turunen et al.,
deficient mice with MDA-LDL induced humoral (2015)
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immune response, IgM and IgG production,
and led to diminished atherosclerosis
C57BL/6 P. gingivalis P. gingivalis infection stimulates PCSK9 Miyazawa et al.,
expression through activation of Srebf2 (2012b)
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associated with degradation of LDLR and
hypercholesterolemia
ApoE- Immunization with Peptide 14 plays proatherogenic role (through
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deficient peptides from P. induction of Th1 cells) while peptide 19 plays (2015)
gingivalis GroEL anti-atherogenic role (through induction of
Tregs)
ApoE- P. gingivalis P. gingivalis could access murine brain and Poole et. al.
deficient F. nucleatum induce complement activation and brain (2015)
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(monoinfection and
polyinfection)
ApoE- T. forsythia or BspA T. forsythia or BspA causes accelerated Lee et al.,(2014)
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ApoE- A. Infection does not influences plaque size and Tuomainen et
deficient actinomycetemcomitans progression but induces elevated CRP levels, al., (2008)
atherogenic lipid profile (increased VLDL and
LDL and decreased LDL), and increase in
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aortic MMP-9 expression
ApoE +/- P. gingivalis Treatment of P. gingivalis-induced Madan et al.,
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atherosclerosis with doxycycline results in (2007)
reduction of plaque area, percentage of
aromathous lesions, levels of proinflammatory
cytokines, and MMP-9
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ApoE- P. gingivalis Arg-gingipain from P. gingivalis specifically Hashimoto et
deficient cleaves ApoB-100 inducing formation of al., (2006)
foam cells, lipid accumulation, increase in
LDL cholesterol, decrease in HDL
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cholesterol, and atherosclerosis progression
ApoE- P. gingivalis P. gingivalis accelerates early atherosclerosis Miyamoto et al.,
deficient accompanied with increased macrophage (2006)
infiltration, atheroma development, and
stimulation of innate immunity but without
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