Periodontitis and cardiovascular diseases: The link and relevant mechanisms

This paper reviews the association between periodontitis and CVD. In addition, the potential mechanisms of any association between periodontitis and CVD as well as the effects of periodontal treatment on CVD are herein discussed. Among the studies carried out by this group and others on coronary artery diseases, peripheral arterial diseases, abdominal aortic aneurysm, and Buerger's disease, periodontopathic bacteria were frequently detected in the diseased blood vessels, thus suggesting an association between periodontitis and CVD. The potential mechanisms of the association between periodontitis and CVD are not fully elucidated. However, inflammation and some autoimmune mechanisms, including molecular mimicry between the periodontopathic bacteria and host molecules, are suggested. The effects of periodontal treatment on CVD might thus vary among the different treatment modalities, and full-mouth mechanical debridement might induce strong transient systemic inflammatory responses in comparison to the quadrant-wise mechanical debridement

Thrombospondin-1 Production Is Enhanced by <i>Porphyromonas gingivalis</i> Lipopolysaccharide in THP-1 Cells

<div><p>Periodontitis is a chronic inflammatory disease caused by gram-negative anaerobic bacteria. Monocytes and macrophages stimulated by periodontopathic bacteria induce inflammatory mediators that cause tooth-supporting structure destruction and alveolar bone resorption. In this study, using a DNA microarray, we identified the enhanced gene expression of thrombospondin-1 (TSP-1) in human monocytic cells stimulated by <i>Porphyromonas gingivalis</i> lipopolysaccharide (LPS). TSP-1 is a multifunctional extracellular matrix protein that is upregulated during the inflammatory process. Recent studies have suggested that TSP-1 is associated with rheumatoid arthritis, diabetes mellitus, and osteoclastogenesis. TSP-1 is secreted from neutrophils, monocytes, and macrophages, which mediate immune responses at inflammatory regions. However, TSP-1 expression in periodontitis and the mechanisms underlying TSP-1 expression in human monocytic cells remain unknown. Here using real-time RT-PCR, we demonstrated that TSP-1 mRNA expression level was significantly upregulated in inflamed periodontitis gingival tissues and in <i>P. gingivalis</i> LPS-stimulated human monocytic cell line THP-1 cells. TSP-1 was expressed via Toll-like receptor (TLR) 2 and TLR4 pathways. In <i>P. gingivalis</i> LPS stimulation, TSP-1 expression was dependent upon TLR2 through the activation of NF-κB signaling. Furthermore, IL-17F synergistically enhanced <i>P. gingivalis</i> LPS-induced TSP-1 production. These results suggest that modulation of TSP-1 expression by <i>P. gingivalis</i> plays an important role in the progression and chronicity of periodontitis. It may also contribute a new target molecule for periodontal therapy.</p></div

MG-132 inhibited TSP-1 mRNA expression in THP-1 cells.

<p>THP-1 cells were pretreated with 5.0 ng/ml of MG-132 (inhibitor of NF-κB) for 1 h, followed by the addition of 1.0 µg/ml of <i>P. gingivalis</i> LPS and 10 ng/ml of IL-17F. <i>P. gingivalis</i> LPS-induced TSP-1 mRNA was significantly reduced by MG-132. MG-132 also significantly reduced TSP-1 mRNA expression induced by <i>P. gingivalis</i> LPS together with IL-17F.</p

Effect of various cytokines on TSP-1 expression in THP-1 cells.

<p>THP-1 cells were co-stimulated with 1.0 µg/ml of <i>P. gingivalis</i> LPS and 10 ng/ml of each of IL-4, IL-17A, IL-17F, or IFN-γ for 4 h. TSP-1 mRNA expression was significantly enhanced by all co-stimulatory factors (<i>P</i><0.001). In particular, TSP-1 mRNA expression by <i>P. gingivalis</i> LPS together with IL-17F was high.</p

Upregulation of TSP-1 in THP-1 cells by <i>P. gingivalis</i> LPS stimulation.

<p>(A) THP-1 cells were stimulated by <i>P. gingivalis</i> LPS at concentrations of 0, 0.0001, 0.001, 0.01, 0.1, or 1.0 µg/ml for 4 h. <i>P. gingivalis</i> LPS increased TSP-1 mRNA expression in a dose-dependent manner in THP-1 cells. (B) THP-1 cells were stimulated by 1.0 µg/ml of <i>P. gingivalis</i> LPS for 0, 1, 2, 4, 12, 24, 48, or 72 h. <i>P. gingivalis</i> LPS increased TSP-1 mRNA expression in a time-dependent manner in THP-1 cells. (C) THP-1 cells were stimulated with <i>P. gingivalis</i> LPS at concentrations of 0, 0.01, 0.1, or 1.0 µg/ml for 72 h. <i>P. gingivalis</i> LPS increased TSP-1 protein production in a dose-dependent manner in THP-1 cells. (D) THP-1 cells were stimulated with 1.0 µg/ml of <i>P. gingivalis</i> LPS for 0, 1, 4, 6, 12, 24, 48, or 72 h. <i>P. gingivalis</i> LPS increased TSP-1 protein production in a time-dependent manner in THP-1 cells. (E) PMA-treated THP-1 cells were stimulated with <i>P. gingivalis</i> LPS at concentrations of 0, 0.01, 0.1, or 1.0 µg/ml for 72 h. <i>P. gingivalis</i> LPS increased TSP-1 protein production in a dose-dependent manner in PMA-treated THP-1 cells.</p

The level of TSP-1 mRNA expression was significantly upregulated in periodontitis gingival tissues.

<p>Human gingival tissues were obtained from periodontal surgical operations. TSP-1 mRNA expression was enhanced in inflammatory gingival tissues. Its expression was significantly higher in regions of deep periodontal pockets than in shallow periodontal pockets and healthy sites (<i>P</i><0.001).</p