The Roles of Periodontal Bacteria in Atherosclerosis

Abstract

Atherosclerosis (AS) is an inflammatory vascular disease that constitutes a major underlying cause of cardiovascular diseases (CVD) and stroke. Infection is a contributing risk factor for AS. Epidemiological evidence has implicated individuals afflicted by periodontitis displaying an increased susceptibility to AS and CVD. This review concisely outlines several prevalent periodontal pathogens identified within atherosclerotic plaques, including Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Fusobacterium nucleatum. We review the existing epidemiological evidence elucidating the association between these pathogens and AS-related diseases, and the diverse mechanisms for which these pathogens may engage in AS, such as endothelial barrier disruption, immune system activation, facilitation of monocyte adhesion and aggregation, and promotion of foam cell formation, all of which contribute to the progression and destabilization of atherosclerotic plaques. Notably, the intricate interplay among bacteria underscores the complex impact of periodontitis on AS. In conclusion, advancing our understanding of the relationship between periodontal pathogens and AS will undoubtedly offer invaluable insights and potential therapeutic avenues for the prevention and management of AS.

Keywords: Aggregatibacter actinomycetemcomitans; CVD; Fusobacterium nucleatum; Porphyromonas gingivalis; atherosclerosis; instability; periodontal pathogens; plaque.

Figure 1

The mechanisms of Pg in AS. Pg infection leads to upregulation of adhesion molecules and chemokine secretion in ECs [70,71,72,84,88,89,90], promoting adhesion and aggregation of monocytes in the bloodstream [83,84,85,86,87]. Pg can activate autophagy in ECs, allowing it to evade immune responses by residing in autophagic vesicles [73,74]. Pg also inhibits EC proliferation [76], promotes EC apoptosis [75,76,77,78], epithelial–mesenchymal transition [65], oxidative stress, and inflammatory factor secretion [46,81,82], ultimately disrupting the vascular endothelial barrier. Under Pg stimulation, macrophages produce more inflammatory mediators [92], leading to increased lipid deposition [93,94,95,96,97,98,99] and exacerbating the inflammatory environment within the plaque. Pg promotes proliferation [103,107], phenotypic transformation [100,106,107], and calcification [104] of VSMCs. Pg-induced imbalance in the differentiation of Th17 and Treg cells worsens inflammation within the plaque [63]. Increased secretion of MMP9 by macrophages promotes collagen degradation and plaque instability [109]. Pg promotes platelet aggregation and thrombus formation by interacting with IgG and Fc γRIIa receptors [111] (drawn by Figdraw).

Figure 2

The mechanisms of Aa in AS. Aa infection upregulates the expression of adhesion molecules ICAM-1 and VCAM-1 in ECs, promoting adhesion and aggregation of monocytes to subendothelium. Aa also induces apoptosis in EC, leading to disruption of the vascular endothelial barrier. Under Aa stimulation, macrophages exhibit increased secretion of inflammatory cytokines and foam cell formation. Aa also promotes macrophage pyroptosis (drawn by Figdraw).

Figure 3

The mechanisms of Fn in AS. Fn infection disrupts the intercellular connections between EC, simultaneously inhibiting EC proliferation and promoting EC apoptosis, leading to increased endothelial permeability. Fn also upregulates the expression of adhesion molecules and chemokines in EC, promoting the adhesion and migration of monocytes toward the sub-endothelial space. Under Fn stimulation, macrophages undergo M1 polarization, resulting in increased production of inflammatory mediators. Macrophage lipid deposition and cell apoptosis are also heightened, fostering the progression of plaque enlargement and an inflammatory environment within the plaque. (Draw by Figdraw).

Figure 4

An overview of the mechanisms of Pi, Tf, Td, and Cr in AS. Td infection induces the secretion of IL-8 and MCP1 by ECs, promoting the adhesion and aggregation of monocytes towards the sub-endothelial space. Pi, Cr, and Tf can activate macrophages via the TLR2/4 signaling pathway, leading to increased production of inflammatory mediators. Additionally, Tf can also promote macrophage-derived foam cell formation induced by ox-LDL (drawn by Figdraw).