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Kozarov et al. Vessel Plus 2020;4:10 I http://dx.doi.org/10.20517/2574-1209.2019.31 Page 7 of 18

quantitative polymerase chain reaction, it was shown that bacterial DNA was present in atherosclerotic
plaque and - of note - the amount of this DNA correlated with the amount of leukocytes in the
[82]
atherosclerotic plaque .
Bacteria possess a profound ability to disrupt the host homeostasis. For example, infection with P. gingivalis
[83]
induces procoagulant effects in human endothelial cells . Very important, an invasive, but not a non-
[84]
invasive, P. gingivalis strain accelerated atherosclerosis in a murine model , pointing to the significance of
strain-specific genomic virulence determinants. Furthermore, it was found that P. gingivalis invasion (but
[45]
not a non-invasive mutant) in ApoE (±) mice was critical for atherosclerosis progression .
[85]
Bacterial infection can also cause apoptosis in endothelia . There is a large body of evidence that P.
gingivalis has developed an elaborate proteolytic system composed of surface-located or secreted enzymes,
Rgp and Kgp gingipains, which serve to provide these asaccharolytic bacteria with sole source of nutrients
in the form of small peptides and amino acids, thus functioning as virulence factors leading to tissue
destruction [86-88] . Consequently, the proteolytic activities of this infectious agent may also contribute to
vascular disruption and subsequent obstruction of the lumen.

At the same time, P. gingivalis cytotoxic activities have been well characterized and loss of cell adhesion
[89]
properties with subsequent apoptotic cell death has been observed [90-92] . Even more aggravating, P. gingivalis
efficiently activates coagulation factors, thus promoting platelet aggregation [93-96] . Thus, internalized
destructive platelet-aggregating inflammatory agent such as P. gingivalis combined with macrophage
infiltration in intimal regions would likely contribute to triggering apoptosis and formation of necrotic
core, potentially leading to plaque weakening and rupture, folloed by triggering of the coagulation cascade,
thrombosis and acute ischemic events.

The Rgp gingipains of P. gingivalis lyse lipoproteins producing 2 apoE fragments, as well as 2 apoB-100
fragments, in LDL, while the Kgp gingipain lyses HDL, induce reactive oxygen species (ROS) and degrade
antioxidants. In addition, both Rgp and Kgp gingipains induce lipid peroxidation. Thus, P. gingivalis may
[97]
affect the lipoproteins expression in blood, another facet of its contribution to atherogenesis . Similarly,
Pep19 from P. gingivalis HSP60 has a distinct ability to induce native-LDL oxidation which may serve as a
plausible mechanism by which this peptide may drive epitope spreading to the neoantigen, i.e., oxidized
[98]
LDL, in the pathogenesis of atherosclerosis .
During endodontic (apical PD) infection, ligation of toll-like receptors (TLRs) on phagocytes’ surface
triggers activation of humoral and cellular responses and also phagocytosis, synthesis of ROS and
production of inflammatory mediators, cytokines and matrix metalloproteinases. TLRs provide innate
immune sensing of conserved pathogen-associated molecular patterns. TLR - mediated signaling also
contribute importantly to cardiovascular disease. For a recent review of this particular subject, see .
[99]
Specifically, oxidative stress has been strongly involved in the pathogenesis of atherosclerosis . The ROS-
[100]
producing systems in the vasculature include reduced nicotinamide adenine dinucleotide phosphate
oxidase, xanthine oxidase, the mitochondrial electron transport chain, and nitric oxide (NO) synthase.
Oxidative stress due to ROS overproduction contributes to all stages of atherogenesis, from the plaque
formation to the most critical stage, the plaque rupture [101-103] . All cardiovascular risk factors such as
hypercholesterolemia, hypertension, diabetes mellitus, and smoking increase ROS and decrease endothelial
NO synthesis .
[104]

Bacterial pathogens can cause oxidative stress via triggering LDL oxidation at the atherosclerotic lesion.
In addition to hematogenous dissemination to the atheroma, bacteria may spread in the system while