Is Porphyromonas gingivalis Cell Invasion Required for Atherogenesis? Pharmacotherapeutic Implications

Abstract

Various studies have demonstrated an association between chronic bacterial infections and atherosclerotic cardiovascular disease. Porphyromonas gingivalis, which can invade endothelial cells, is one pathogen that may link these disorders. If so, antibiotics that block its invasiveness may ameliorate atherosclerotic plaque progression. To explore the role of invasion of P. gingivalis in inflammation- and infection-associated atherosclerosis, 10-wk-old ApoE+/− mice were fed either a high fat diet or a regular chow diet. All mice were inoculated i.v., once per week for 24 consecutive wk, with either 50 μl of live P. gingivalis (strain 381) (107 CFU); a fimbria-deficient P. gingivalis; or metronidazole before P. gingivalis. Mice were euthanized and evaluated 24 wk after the first inoculation. ApoE+/− mice injected with DPG3 or metronidazole showed significantly fewer atheromatous lesions in the proximal aorta and the aortic tree compared with ApoE+/− mice injected with wild-type P. gingivalis for either diet condition. Serum amyloid A levels were significantly lower in ApoE+/− mice that received either DPG3 or metronidazole before P. gingivalis than from ApoE+/− mice that received P. gingivalis alone. Serum cytokine analysis revealed decreased levels of proinflammatory cytokines in both DPG3-injected and metronidazole/P. gingivalis-treated ApoE+/− mice compared with mice receiving only P. gingivalis, irrespective of diet. P. gingivalis invasion is a critical phenomenon in the progression of atherosclerosis. The present data offer new insights into the pathophysiological pathways involved in atherosclerosis and pave the way for new pharmacological interventions aimed at reducing atherosclerosis.

Pivotal role of NOD2 in inflammatory processes affecting atherosclerosis and periodontal bone loss

“…identified in atherosclerotic plaques of patients suffering from atherosclerosis, suggesting that this pathogen might be critical for atheroma formation (18). Indeed, we showed that endothelial dysfunction associated with repetitive exposure by P. gingivalis can exacerbate the development of atherosclerosis (19).…”

Inflammatory Bone Loss in Experimental Periodontitis Induced by Aggregatibacter actinomycetemcomitans in Interleukin-1 Receptor Antagonist Knockout Mice

“…Alveolar bone resorption may (42,43) or may not (44,45) be recognized in inbred strains of mice challenged by oral Porphyromonas gingivalis infection. Moreover, normal Wistar rats exhibited no alveolar bone loss induced by oral A. actinomycetemcomitans infection (46).…”

The Atherogenic BacteriumPorphyromonas gingivalisEvades Circulating Phagocytes by Adhering to Erythrocytes

“…Adherence of P. gingivalis to endothelial cells has been shown to depend on major and minor fimbriae on the bacterial surface (8,11). Accordingly, atheromatous lesions can be induced in mouse aortas by in vivo injection with wild-type P. gingivalis, whereas significantly fewer lesions are observed when fimbria-deficient strains of the bacterium are injected (1). P. gingivalis invasion of endothelial cells leads to increased autocrine production of IL-6, a cytokine with a well-established role in the regulation of atherosclerotic disease (16).…”

“…These mediators activate circulating neutrophils and monocytes and induce release of procoagulant factors from the endothelium. Mice injected with wild-type P. gingivalis develop atheromatous lesions in the aorta, and markedly fewer lesions are observed if metronidazole is administered before injection or if a fimbria-deficient strain of P. gingivalis is used (1). DNA from P. gingivalis has been found in specimens of atherosclerotic plaques removed from carotid and femoral arteries during surgery (23,43), suggesting that the innate immune system is occasionally incapable of limiting P. gingivalis infections to the periodontal tissues.…”