Epidemiologic studies suggest a link between periodontitis and increased risk of atherosclerosis in human subjects. Hypotheses to account for these observations include systemic inflammation primed by local periodontal infection and release of lipopolysaccharide (LPS) into the periphery, thereby activating circulating inflammatory cells, platelets and endothelial cells; direct invasion of pathogenic bacteria in the vessel wall consequent to bouts of transient bacteremia; exaggerated, """"""""hyper"""""""" immune responses to periodontal bacteria or cross-reactivity between microbial and human antigens; or underlying predisposing mechanisms, such as genetic predilection. Most likely, interactions of these mechanisms underlie accelerated atherosclerosis in periodontal infection. Atherogenesis is a multi-stage process initiated by interaction of pathogenic lipoproteins with the vessel wall. Superimposed injury, may exaggerate the host response and accelerate atherosclerosis. To dissect the contribution of periodontal infections to accelerated vascular disease, we employed the hypercholesterolemic apolipoprotein (apo) E null mouse. Mice were subjected to oral inoculation with the periodontal pathogen Porphyromonas gingivalis, stain 381, (P. gingivalis) at age 6 weeks; at age 17 weeks, atherosclerotic lesion number and area at the aortic sinus were increased in infected vs. uninfected mice. In parallel with increased atherosclerosis, infected mice displayed serum antibody (IgG) response to P gingivalis; increased alveolar bone loss and elevated levels of plasma IL-6 (both correlating with extent of atherosclerotic lesion area); bacterial localization in the aorta by polymerase chain reaction; and increased tissue factor and Vascular Cell Adhesion Molecule-1 antigens, and increased antigen and activity of matrix metalloproteinase-2 in aortic extracts. Levels of plasma lipids, insulin and creatinine did not differ between infected vs. uninfected mice. Pilot studies suggest that apo E null mice infected with the fimbriae-deficient mutant of P. gingivalis 381, DPG-3, do not demonstrate increased atherosclerosis; thus, adhesion/invasion of host cells by bacteria may critically contribute to acceleration of atherogenesis by P. gingivalis. We posit that multiple mechanisms underlie accelerated atherosclerosis in periodontal disease, including systemic responses to local (periodontal) injury in inflammatory cells, platelets and the vascular endothelium, and direct invasion of bacteria into the vessel wall. We propose to employ this model to dissect the factors accelerating vascular inflammation and atherosclerosis in periodontitis.
