Cariogenic and periodontal pathogens are thought to be etiological factors in the development of cardiovascular disease. We assessed the involvement of the periodontal pathogen Aggregatibacter actinomycetemcomitans and cariogenic pathogen Streptococcus mutans in the development of atherosclerosis in apolipoprotein E-deficient spontaneously hyperlipidemic (Apoe(shl)) mice. The mice were treated intravenously with A. actinomycetemcomitans HK1651, S. mutans GS-5, or phosphate-buffered saline three times a week for 3 weeks and killed at 15 weeks of age. The areas of the aortic sinus that were covered with atherosclerotic plaque were significantly larger in Apoe(shl) mice challenged with A. actinomycetemcomitans compared with S. mutans- or vehicle-challenged mice. Aggregatibacter actinomycetemcomitans challenge increased serum high-sensitive C-reactive protein and lipopolysaccharide levels. Bacterial DNA was detected in the blood, heart, and spleen, but not in the liver. Furthermore, serum interleukin-6 (IL-6), IL-8, tumor necrosis factor alpha, and MCP-1 levels and Toll-like receptor (TLR)2, TLR4, ICAM-1, E-selectin, P-selectin, LOX-1, HSP60, CCL19, CCL21, CCR7, and MCP-1 expressions in the aorta were significantly increased in mice challenged with A. actinomycetemcomitans. These results suggest that systemic infection with A. actinomycetemcomitans accelerates atherosclerosis in Apoe(shl) mice by exposing the whole microorganisms or their products, followed by initiating inflammation. Increases in proatherogenic factors may explain the aggravation of atherosclerosis by A. actinomycetemcomitans infection.

In this study, we demonstrated that the 40-kDa outer membrane protein of Porphyromonas gingivalis (40-kDa OMP) nasally administered with a nontoxic chimeric adjuvant that combines the A subunit of mutant cholera toxin E112K with the pentameric B subunit of heat-labile enterotoxin from enterotoxigenic Escherichia coli (mCTA/LTB) elicited a long-term protective immune response. Immunization with the 40-kDa OMP and mCTA/LTB induced high levels of 40-kDa-OMP-specific immunoglobulin G (IgG) and IgA antibodies (Abs) in sera and elicited a significant IgA anti-40-kDa OMP Ab response in saliva. These Ab responses were maintained for at least 1 year after the immunization. Although using adjuvant mCTA/LTB gave Ab responses in the saliva comparable to those obtained using native cholera toxin (nCT) as the adjuvant, the levels of total IgE and 40-kDa-OMP-specific IgE Abs as well as interleukin-4 levels induced by the immunization with mCTA/LTB were lower than those induced by the immunization with nCT. Importantly, IgG Abs generated by nasal immunization with the 40-kDa OMP plus mCTA/LTB inhibited the coaggregation and hemagglutinin activities of P. gingivalis. Furthermore, the mice given nasal 40-kDa OMP plus mCTA/LTB showed a significant reduction of alveolar bone loss caused by oral infection with P. gingivalis even 1 year after the immunization compared to the loss in unimmunized mice. Because mCTA/LTB is nontoxic, nasally administered 40-kDa OMP together with mCTA/LTB should be an effective and safe mucosal vaccine against P. gingivalis infection in humans and may be an important tool for the prevention of chronic periodontitis.Chronic periodontitis is a common oral inflammatory disease that causes the breakdown of periodontal tissue, including the resorption of alveolar bone, and as a consequence, tooth loss (8). Furthermore, recent studies have suggested that chronic periodontitis influences systemic conditions such as cardiovascular diseases, diabetes, and osteoporosis (5,10,19,28,39,41,45). Hence, the prevention of periodontitis is important for both oral and systemic health.Porphyromonas gingivalis, a gram-negative anaerobic bacterium, has been shown previously to be one of the major pathogens in chronic periodontitis. The colonization of gingival tissues by this bacterium is considered to be the first step in the pathogenic process of periodontal disease resulting in tissue destruction (24, 37). Molecules such as fimbriae, hemagglutinins, aggregation factors, and lipopolysaccharides responsible for colonization have been identified previously as virulence factors (24,37). An outer membrane protein having a molecular mass of 40 kDa produced by P. gingivalis (40-kDa OMP) is a key virulence factor involved in the coaggregation activity of P. gingivalis (23). Furthermore, this OMP has been shown previously to be a hemin-binding protein (49). The 40-kDa OMP resides both on the cell surface and in extracellular vesicles and is found on many strains of P. gingivalis (1,22,23,47).Previous studies have demonstrated that ...

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Monocyte recruitment to the endothelium is a crucial step in the inflammatory response that precedes the development of atherosclerosis. We assessed the effect of Porphyromonas gingivalis on monocyte adhesion to endothelial cells, cytokine production during monocyte/endothelial cell co-culture, and the expression of cell adhesion molecules on human umbilical vein endothelial cells (HUVEC) and their ligands on monocytes. Porphyromonas gingivalis challenge significantly increased the adhesion of THP-1 monocytes to HUVEC, the production of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein 1 (MCP-1) in co-cultures of HUVEC and THP-1 cells, and the transcription and translation of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in HUVEC. The transcription of tumor necrosis factor receptor-associated factor 1 was also increased in HUVEC and THP-1 cells by P. gingivalis infection. Moreover, the stimulation of monocyte adhesion to HUVEC by P. gingivalis infection was partially inhibited by pretreatment with a mixture of anti-ICAM-1, -VCAM, and -E-selectin monoclonal antibodies. These data suggest that adherence between HUVEC and THP-1 cells, followed by the production of cytokines and chemokines, was enhanced by increased expression of cell adhesion molecules on P. gingivalis-sensitized HUVEC, which in turn led to inflammatory atherogenesis.