Mechanisms for Periodontal Disease to Lead to an Increased Risk of Atherosclerosis: Analytical Essay

Through which mechanisms might periodontal disease lead to an increased risk of atherosclerosis?

Introduction

Periodontal disease is the irreversible chronic inflammation of surrounding and supporting structures of teeth (periodontal ligament) and it affects around 20-25% of the global population (Nazir. MA, 2017), it’s caused due to the infection from various gram-negative anaerobic bacteria, mainly; Porphyromonas gingivalis and Treponema denticola. They create a biofilm layer which later develops into subgingival plaque, leading to alveolar bone resorption and ultimately exfoliation of teeth, these are characteristic features of periodontitis.

Atherosclerosis is also a chronic inflammatory condition which occurs as a result of hyperlipidemia, it is characterized by plaque deposits known as atheroma in major arteries. The process by which atherosclerotic plaque develops is demonstrated in figure 1, It’s a multifactorial process, with one of the debated risk factors being periodontal disease and thereby the mechanism of its involvement in the pathogenesis of atherosclerosis.

There have been several epidemiological studies which highlight an association between these two chronic inflammatory conditions, concluding that periodontal disease increases the risk and accelerates the progression of atherosclerosis (Miyaki et al. 2006, Ahn et al. 2016). In this review, I aim to explore the key mechanisms that studies have previously covered regarding this association. Many pathophysiological pathways have been proposed with regards to the link between periodontal disease and atherosclerosis, they can be divided into direct; bacteremia/endotoxemia as well as bacterial invasion and activation of endothelial cells and indirect mechanisms; molecular mimicry/autoimmunity and induction of inflammation.

Figure 1 (Xu. S, et al. 2016) – illustrates the process of atherogenesis; it involves adhesion of monocytes to the endothelial cell surface, migration of monocytes to the subendothelial space, ingestion of LDLs by macrophages leading to formation of foam cells which are characteristic of atherosclerosis, together with T cells form a fatty streak, smooth muscle cells migrate from the media to the intima and proliferate as the lesion progresses to form atherosclerotic plaques.

Figure 2 (Chistiakov et al. 2016) – This figure summarises the effects periodontal pathogens have on host cells with regards to the pathogenesis and progression of atherosclerosis

Direct mechanisms

Bacteremia/endotoxemia

Bacteraemia refers to the presence of bacteria in systemic circulation whilst endotoxemia is the presence of endotoxins (bacterial components) within systemic circulation. Given that the periodontal tissue is very well vascularized, which aids the entrance of periodontal pathogens into the bloodstream, this process occurs with such ease that it has been found that both bacteria and endotoxins from the oral cavity can enter systemic circulation during processes as simple as mastication and flossing (Geerts, SO. et al. 2002; Crasta, K. et al. 2009). Once within the bloodstream the bacteria and endotoxins either circulate the blood extracellularly or bound to a phagocytic cell before they are deposited to have their effects on various cells to promote atherogenesis, figure 2. Periodontal pathogens, including P.gingivalis, have been identified within atheroma using PCR (Haraszthy, V.I. et al. 2000), not only indicating the presence of periodontal pathogens within systemic circulation but also their involvement in atherogenesis.

Invasion and activation of endothelial cells

Once within the bloodstream, the periodontal pathogens must evade the host’s immune system in order to have their effect, one of the ways in which they do this is by the invasion of endothelial cells. A pioneering study by Deshpande et al. (1998) proved the ability of P.gingivalis to invade human umbilical vein endothelial cells (HUVEC) in a highly efficient process which requires the expression of major fimbriae (41 kDa) for both adherence and invasion of the endothelial cells. A two-step process for the interaction of P.gingivalis with host cells was been proposed; initial attachment mediated via 41 kDa major fimbriae, followed by a more intimate interaction mediated by minor fimbriae facilitating endocytosis of P.gingivalis. (Lamont and Jenkinson 1998. Njoroge et al. 1997. Takashaki et al. 2005). T.denticola has also shown the ability to invade endothelial cells via endocytosis, the pathogen was identified within endothelial cells using fluorescent in situ hybridization (FISH) of atherosclerotic plaque (Chukkapalli et al. 2014).

Once within the endothelial cells, the periodontal pathogens cause a series of events to initiate and promote atherogenesis. T.denticola causes a significant increase in known atherosclerotic risk factors, including VLDL, oxidized LDL serum levels, and pro-inflammatory mediators, leading to initiation of plaque formation following hyperlipidemia (Chukkapalli et al. 2014).

P.gingivalis causes increased monocyte chemoattractant protein-1 (MCP-1) secretion from endothelial cells (Kang and Kuramitsu, 2002), the role of MCP-1 is to cause the transmigration of monocytes through endothelial cells which ultimately leads to the formation of foam cells, these are characteristic of atheroma (figure 1). But for MCP-1 production to occur P.gingivalis must express major fimbriae (41kDa) as this only occurs once P.gingivalis is within the endothelial cell, and as mentioned, invasion of endothelial cells is fimbriae-mediated. This was confirmed when endothelial cells were cocultured with P.gingivalis whilst inhibiting endocytosis, the result was that no MCP-1 was produced (Takahashi et al. 2005). Other pro-inflammatory molecules are also produced during this interaction including; IL-1β, IL-8, ICAM-1, VCAM-1, and E-selectin (Takahashi et al. 2005). The mechanism by which these chemokines were produced is unclear, but the basis is due to cytoskeleton rearrangement. T.denticola was also found to induce the production of IL-8 and MCP-1 in endothelial cells by stimulating mRNA expression, transcription, and translation ultimately leading to the progression of atheroma formation (Okuda et al. 2007). The production of these chemokines is one of the first steps in developing an early atherosclerotic lesion.

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Interestingly, Nassar et al. (2002) found that P.gingivalis can modulate the production of chemokines and adhesion molecules including; MCP-1 and IL-8, intracellular adhesion molecules (ICAM-1), and vascular cellular adhesion molecules (VCAM-1) in endothelial cells via fimbriae- and gingipain-mediated mechanisms, more specifically lysine-specific cysteine proteinase (gingipain K). Gingipains are a group of proteases secreted by P.gingivalis and their primary function is to degrade cytokines hence downregulating the host’s immune response. However, it was later discovered that endothelial cells treated with gingipains secreted by P.gingivalis exhibited a rapid loss of cell adhesion properties followed by apoptosis, hence causing detachment and death of these cells (Sheets et al. 2005). The stark difference between these two findings are likely due to the type of endothelial cells that were used; Nassar et al. used HUVEC whilst Sheets et al. used human arterial endothelial cells (HAEC), due to chemical differences between these two cells and given that atheroma develop within arteries rather than veins, it is reasonable to assume the findings of Sheets et al. to be more applicable to atherogenesis with regards the effects of gingipains on arterial endothelial cells. This would lead to vascular tissue destruction, which is indicated in atherosclerotic lesion progression, figure 1.

Indirect mechanisms

Molecular mimicry/autoimmunity

Molecular mimicry is the process by which an autoimmune response is initiated due to similarities in amino acid sequence between self-molecules and foreign antigens, this process involves the activation of T and B lymphocytes (Froude J et al, 1989). With regards to atherogenesis, molecular mimicry would involve the targeting of the host’s immune response against the host proteins expressed by endothelial cells in the vascular wall. Arterial endothelial cells express human heat shock protein 60 (hHSP60) on their cell surface in response to stress factors such as temperature or infection, the function of hHSP60 is to initiate an intracellular signaling cascade which mediates a range of inflammatory responses including the release of cytokines. Bacteria, including the periodontal pathogen P.gingivalis, express bacterial heat shock proteins known as GroEL, both these proteins are very well conserved meaning their sequences do not differ much between species. It has been proposed that cross-reactivity of the host’s immune response between hHSP60 and bacterial GroEL occurs (Ford P.J. et al. 2005; Ford P et al., 2004), meaning the host’s anti-P. gingivalis GroEL antibodies have been found to induce an immune response against stressed endothelial cells which ultimately leads to endothelial cell dysfunction hence atherosclerosis progression.

A study was undertaken to investigate the proposed cross-reactivity reaction. The results showed that anti-P.gingivalis antibodies levels were significantly higher in atherosclerosis patients with advanced periodontitis compared to those with periodontal health (Yamazaki et al. 2004). Clonal analysis of the T cells demonstrated the presence of both hHSP60- and GroEL-reactive T-cell populations within systemic circulation of the atherosclerosis patients who also suffer from periodontitis, they were also found within periodontal pockets and atherosclerotic plaque lesions. This indicates that both these T cells may have similar specificity to both hHSP60 and GroEL, and so anti-P. gingivalis GroEL antibodies can react with hHSP60 expressed on injured endothelial cells and therefore are both involved in the pathogenesis of atherosclerosis by means of endothelial cell dysfunction.

In addition, Th1 and Th2 cells specific to P.gingivalis GroEL were extracted from atherosclerotic lesions of periodontitis patients indicating that the immune response to this bacterium is involved in the pathogenesis of atherosclerosis (Choi J.I. et al. 2002)

Induction of inflammation

The presence of periodontal pathogens in systemic circulation has been shown to also influence the inflammatory stage of atherogenesis; more specifically in the development of an early atherosclerotic lesion (figure 1). The ways in which this inflammation is induced has been found to be as follows:

Toll-like receptors (TLRs) are involved in the innate immune system when activated they induce a signalling cascade which induces production of pro-inflammatory cytokines hence an immune response. P.gingivalis causes increased expression of TLR2, TLR3, TLR4, TLR6, and TLR9 on the surface of endothelial cells upon fimbriae-dependent invasion of endothelial cells (Yumoto H, et al 2005). It has also been found that more specifically TLR2 and TLR4 are heavily involved in inducing an inflammatory response characteristic of early atherosclerotic lesions specifically inflammatory activation of endothelial cells and macrophages (Edfeldt K. et al. 2002)

Release of TNF-α and IL-1β systemically occurs due to systemic exposure to gram-negative bacteria specifically LPS that these bacteria express which are involved in the pathogenesis of periodontal disease following bacteremia and endotoxemia (Hesse D.G. et al. 1988; Michie H.R. et al. 1988; Koopmans R. et al. 1994; Iacopino A.M., and Cutler C.W., 2000). These 2 cytokines are involved in the ‘cytokine cascade’ TNF-α being the first factor followed by IL-1β, these indirectly affect lipid production in the liver due to their effect on release of other cytokines hence increasing LDL and free fatty acid serum levels which leads to hyperlipidemia, an undisputed risk factor for atherosclerosis (Van der Poll T and Saurwein HP, 1993; Iacopino A.M., and Cutler C.W., 2000).

Finally, the cytokines released upon endothelial cell activation; IL-1β, IL-8, ICAM-1, VCAM-1, and E-selectin, cause localized inflammation which is one of the key steps in progression of early atherosclerotic lesions.

Conclusion

The mechanisms discussed show biological plausibility and appear to have the capacity to promote atherosclerosis both independently and collectively. The association found in epidemiological studies indicating an increased risk of atherosclerosis in subjects with periodontal disease now has many proposed mechanisms via both direct and indirect effects. These effects are initiated following bacteremia and endotoxemia of periodontal pathogens and their components. Then the bacteria, namely P.gingivalis and T.denticola, can either have direct effects on endothelial cells following their invasion, including; promoting the secretion of pro-inflammatory cytokines IL-8 and MCP-1, causing detachment and apoptosis of endothelial cells in a gingipain-mediated mechanism, both of which lead to progression of atherosclerosis. Or indirect effects which involve: molecular mimicry; induction of the immune system against self-molecules, namely the similar specificity between antibodies directed against hHSP60 and P.gingivalis GroEL, and induction of inflammation both locally and systemically to cause progression of early atherosclerotic lesions.

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