Porphyromonas gingivalis Bacteremia Induces Coronary and Aortic Atherosclerosis in Normocholesterolemic and Hypercholesterolemic Pigs

Abstract

Objectives-The aim of this study was to determine whether recurrent intravenous injections with Porphyromonas gingivalis (P gingivalis), mimicking periodontitis-associated bacteremia, promotes coronary artery and aortic atherosclerosis in pigs. Methods and Results-Pigs (nϭ36) fed low-or high-fat chow were divided into P gingivalis-sensitized and P gingivalis-challenged groups or P gingivalis-sensitized controls and saline-treated controls. Pigs were sensitized with 10 9 killed P gingivalis subcutaneously. Four weeks later all sensitized pigs in the group to be challenged started intravenous injections thrice weekly for 5 months with 10 6 to 10 7 colony forming units of P gingivalis while controls received saline. Anti-P gingivalis antibody, serum cholesterol, and complete blood counts were assayed monthly. Pigs were euthanized 2 weeks after the last injection, and coronary arteries and aortas were analyzed by histomorphometry and immunohistochemistry. Anti-P gingivalis antibody was increased by P gingivalis exposure. P gingivalischallenged pigs developed a significantly greater amount of coronary and aortic atherosclerosis than controls in the normocholesterolemic group and nearly significant in the hypercholesterolemic group. P gingivalis was detected by polymerase chain reaction in arteries from most (94%, 16 of 17) P gingivalis-challenged pigs but not controls. Key Words: coronary and aortic atherosclerosis Ⅲ Porphyromonas gingivalis Ⅲ periodontitis Ⅲ pig model Ⅲ bacteremia P eriodontitis has been associated with cardiovascular disease in many, but not all, epidemiological studies. 1-15 Mild forms of periodontal disease affect 75% of the population, and more severe forms affect 20% to 30% of adults in the United States. 8 The mechanism by which periodontitis could contribute to cardiovascular disease is unknown but likely relates to the associated intense local and systemic inflammation and the virulence properties of the causative organisms. 16 -21 Porphyromonas gingivalis has been strongly associated with adult periodontitis. This bacteria is a Gramnegative, nonmotile, obligate anaerobe that can invade and infect epithelium, endothelium, and vascular smooth muscle cells 22-29 and appears to alter endothelial function. 30 The capacity for invasion is in part mediated by fimbriae, 31,32 and the virulence of P gingivalis may vary among individual strains. 33 Recurrent bacteremias with P gingivalis and a mixture of other oral bacteria can occur in periodontitis patients during simple mastication. 34 -36 P gingivalis has been detected by immunostaining and polymerase chain reaction (PCR) in some human carotid and coronary atheromas. 27,37 In addition, P gingivalis produces arginine-specific cysteine proteases, called gingipain Rs, that can activate both the cellular and humoral coagulation systems. These gingipain Rs activate protease-activated receptors 1 and 4 (PAR-1 and PAR-4) on platelets to a degree sufficient to support ex vivo aggregation. 38 -42 Moreover, gingipain Rs can activate coagulation factors I...

Defining the gut microbiota in individuals with periodontal diseases: an exploratory study

“…Periodontal pathogens, such as Aggregatibacter actinomycetemcomitans, Treponema denticola and Porphyromonas gingivalis are also capable of invading endothelial cells [23–27], and they have been detected in atherosclerotic plaques, heart valves, aortic aneurysms, carotid and coronary vessels [28–33]. Studies in a variety of animal models have demonstrated that recurrent bacteraemia or oral administration with P. gingivalis can enhance atherogenesis [34,35]. Of interest, P. gingivalis is so far the only bacterium capable of causing enzymatic citrullination of peptides with subsequent development of anti-citrullinated peptide auto-antibodies, a major etiopathologic event in RA [36].…”

Involvement of the TREM-1/DAP12 pathway in the innate immune responses to Porphyromonas gingivalis

“…Elevated levels of P. gingivalis are detected in periodontal lesions, and these can be significantly reduced following successful periodontal therapy (Cappelli et al, 2009;Salvi et al, 1997;Socransky et al, 2002;Ximenez-Fyvie et al, 2000;Yamazaki et al, 2004). Apart from its well accepted role as an oral pathogen in the establishment of chronic inflammation at the site of infection, there is increasing evidence of a link between P. gingivalis-associated periodontal disease and systemic inflammatory conditions, such as diabetes, preterm birth, aspiration pneumonia and atherosclerotic cardiovascular disease (Brodala et al, 2005;Liao et al, 2009;Lin et al, 2003;Maekawa et al, 2011;Pussinen and Mattila, 2004). On the cellular level, a convincing body of evidence indicates that P. gingivalis possesses unique signalling properties, which enable it to evade, subvert or manipulate the host immune defences by exploiting the toll-like receptor (TLR) family, in particular TLR2 (Burns et al, 2006;Hajishengallis et al, 2002;Hajishengallis et al, 2008b;Harokopakis et al, 2006;Wang et al, 2010).…”

Mechanisms of Periodontitis - Induced Atherosclerosis

“…[39,40] Researches have demonstrated that PG induction may invade endothel and may initiate atherosclerosis in pigs. [75] The presences of PG in atheroma and human carotid aorta had been detected by immunostaining and PCR. [76,77] PG was known to have fimbriae, which allowed it to invade [51] and stimulate host response to produce citokynes, [52,[78][79][80][81] and may be in latent phase [82] to cause chronic infection in EC and SMC.…”

“…[76,77] PG was known to have fimbriae, which allowed it to invade [51] and stimulate host response to produce citokynes, [52,[78][79][80][81] and may be in latent phase [82] to cause chronic infection in EC and SMC. [75] Chronic infection was known to be able to cause endothelial dysfunction. [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] PG�s fimbriae secretes protein, called gp130, [83] which facilitate PG to invade EC and trigger celluler immune response.…”