Porphyromonas gingivalis disrupts vascular endothelial homeostasis in a TLR-NF-κB axis dependent manner

Abstract

Cardiovascular disease is still the leading cause of mortality worldwide. Vascular endothelial dysfunction is viewed as the initial step of most cardiovascular diseases. Many studies have indicated that periodontal pathogens, especially Porphyromonas gingivalis, are closely correlated with vascular endothelial homeostasis, but the function of P. gingivalis and the underlying mechanisms are still elusive. To illuminate the effects and elucidate the mechanisms of P. gingivalis on endothelial structural integrity, we developed P. gingivalis infection models in vivo and in vitro. Endothelial cell proliferation, differentiation and apoptosis were detected. Here, we showed that P. gingivalis can impair endothelial integrity by inhibiting cell proliferation and inducing endothelial mesenchymal transformation and apoptosis of endothelial cells, which reduce the cell levels and cause the endothelium to lose its ability to repair itself. A mechanistic analysis showed that TLR antagonist or NF-κB signalling inhibitor can largely rescue the damaged integrity of the endothelium caused by P. gingivalis, suggesting that TLR-NF-κB signalling plays a vital role in vascular endothelial homeostasis destroyed by P. gingivalis. These results suggest a potential intervention method for the prevention and treatment of cardiovascular disease.

References

[1] Epelman S, Liu PP, Mann DL. Role of innate and adaptive immune mechanisms in cardiac injury and repair. Nat. Rev. Immunol., 2015, 15: 117-129.

[2] Ruparelia N, Chai JT, Fisher EA, Choudhury RP. Inflammatory processes in cardiovascular disease: a route to targeted therapies. Nat. Rev. Cardiol., 2017, 14: 133-144.

[3] Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med., 2005, 352: 1685-1695.

[4] Frangogiannis NG. Regulation of the inflammatory response in cardiac repair. Circ. Res., 2012, 110: 159-173.

[5] Vink A, . Distribution of Chlamydia pneumoniae in the human arterial system and its relation to the local amount of atherosclerosis within the individual. Circulation, 2001, 103: 1613-1617.

[6] Chen S, . Chlamydia and lipids engage a common signaling pathway that promotes atherogenesis. J. Am. Coll. Cardiol., 2018, 71: 1553-1570.

[7] Shah ASV, . Global burden of atherosclerotic cardiovascular disease in people living with HIV: systematic review and meta-analysis. Circulation, 2018, 138: 1100-1112.

[8] Fournier PE, . Coxiella burnetii infection of aneurysms or vascular grafts: report of seven cases and review. Clin. Infect. Dis., 1998, 26: 116-121.

[9] Natanson C, . Role of endotoxemia in cardiovascular dysfunction and mortality. Escherichia coli and Staphylococcus aureus challenges in a canine model of human septic shock. J. Clin. Invest., 1989, 83: 243-251.

[10] Freitas-Ferraz AB, . Contemporary epidemiology and outcomes in recurrent infective endocarditis. Heart, 2020, 106: 596-602.

[11] Forner L, Larsen T, Kilian M, Holmstrup P. Incidence of bacteremia after chewing, tooth brushing and scaling in individuals with periodontal inflammation. J. Clin. Periodontol., 2006, 33: 401-407.

[12] Czesnikiewicz-Guzik M, . Causal association between periodontitis and hypertension: evidence from Mendelian randomization and a randomized controlled trial of non-surgical periodontal therapy. Eur. Heart J., 2019, 40: 3459-3470.

[13] Ryden L, . Periodontitis increases the risk of a first myocardial infarction: a report from the PAROKRANK study. Circulation, 2016, 133: 576-583.

[14] Vedin O, . Periodontal disease in patients with chronic coronary heart disease: prevalence and association with cardiovascular risk factors. Eur. J. Prev. Cardiol., 2015, 22: 771-778.

[15] Mougeot JC, . Porphyromonas gingivalis is the most abundant species detected in coronary and femoral arteries. J. Oral. Microbiol., 2017, 9: 1281562.

[16] Lanter BB, Sauer K, Davies DG. Bacteria present in carotid arterial plaques are found as biofilm deposits which may contribute to enhanced risk of plaque rupture. mBio, 2014, 5: e01206-e01214.

[17] Pessi T, . Bacterial signatures in thrombus aspirates of patients with myocardial infarction. Circulation, 2013, 127: 1219-1228. e1–e6

[18] Hyvarinen K, . A common periodontal pathogen has an adverse association with both acute and stable coronary artery disease. Atherosclerosis, 2012, 223: 478-484.

[19] Li L, Messas E, Batista EL Jr, Levine RA, Amar S. Porphyromonas gingivalis infection accelerates the progression of atherosclerosis in a heterozygous apolipoprotein E-deficient murine model. Circulation, 2002, 105: 861-867.

[20] Kesavalu L, . Increased atherogenesis during Streptococcus mutans infection in ApoE-null mice. J. Dent. Res., 2012, 91: 255-260.

[21] Cui D, Li H, Lei L, Chen C, Yan F. Nonsurgical periodontal treatment reduced aortic inflammation in ApoE(-/-) mice with periodontitis. Springerplus, 2016, 5

[22] Shiheido Y, . Porphyromonas gingivalis, a periodontal pathogen, enhances myocardial vulnerability, thereby promoting post-infarct cardiac rupture. J. Mol. Cell. Cardiol., 2016, 99: 123-137.

[23] Iwai T. Periodontal bacteremia and various vascular diseases. J. Periodontal Res., 2009, 44: 689-694.

[24] Berggreen E, Wiig H. Lymphangiogenesis and lymphatic function in periodontal disease. J. Dent. Res., 2013, 92: 1074-1080.

[25] Gibson FC 3rd, Yumoto H, Takahashi Y, Chou HH, Genco CA. Innate immune signaling and Porphyromonas gingivalis-accelerated atherosclerosis. J. Dent. Res., 2006, 85: 106-121.

[26] Cahill PA, Redmond EM. Vascular endothelium - gatekeeper of vessel health. Atherosclerosis, 2016, 248: 97-109.

[27] Roth GA, . Infection with a periodontal pathogen increases mononuclear cell adhesion to human aortic endothelial cells. Atherosclerosis, 2007, 190: 271-281.

[28] Sun W, . Porphyromonas gingivalis stimulates the release of nitric oxide by inducing expression of inducible nitric oxide synthases and inhibiting endothelial nitric oxide synthases. J. Periodontal Res., 2010, 45: 381-388.

[29] Kovacic JC, . Endothelial to mesenchymal transition in cardiovascular disease: JACC state-of-the-art review. J. Am. Coll. Cardiol., 2019, 73: 190-209.

[30] Good RB, . Endothelial to mesenchymal transition contributes to endothelial dysfunction in pulmonary arterial hypertension. Am. J. Pathol., 2015, 185: 1850-1858.

[31] Dardik A, . Differential effects of orbital and laminar shear stress on endothelial cells. J. Vasc. Surg., 2005, 41: 869-880.

[32] Maekawa T, . Porphyromonas gingivalis manipulates complement and TLR signaling to uncouple bacterial clearance from inflammation and promote dysbiosis. Cell Host Microbe, 2014, 15: 768-778.

[33] Brown J, Wang H, Hajishengallis GN, Martin M. TLR-signaling networks: an integration of adaptor molecules, kinases, and cross-talk. J. Dent. Res., 2011, 90: 417-427.

[34] Fiordelisi A, Iaccarino G, Morisco C, Coscioni E, Sorriento D. NFkappaB is a key player in the crosstalk between inflammation and cardiovascular diseases. Int. J. Mol. Sci., 2019, 20: 1599.

[35] Pirro M, . Lipoprotein(a) and inflammation: a dangerous duet leading to endothelial loss of integrity. Pharmacol. Res., 2017, 119: 178-187.

[36] Rochfort KD, Collins LE, McLoughlin A, Cummins PM. Tumour necrosis factor-alpha-mediated disruption of cerebrovascular endothelial barrier integrity in vitro involves the production of proinflammatory interleukin-6. J. Neurochem., 2016, 136: 564-572.

[37] Modhiran N, . Dengue virus NS1 protein activates cells via toll-like receptor 4 and disrupts endothelial cell monolayer integrity. Sci. Transl. Med., 2015, 7: 304ra142.

[38] Carroll GC, Sebor RJ. Dental flossing and its relationship to transient bacteremia. J. Periodontol., 1980, 51: 691-692.

[39] Silver JG, Martin AW, McBride BC. Experimental transient bacteraemias in human subjects with varying degrees of plaque accumulation and gingival inflammation. J. Clin. Periodontol., 1977, 4: 92-99.

[40] Lamont RJ, . Porphyromonas gingivalis invasion of gingival epithelial cells. Infect. Immun., 1995, 63: 3878-3885.

[41] Deshpande RG, Khan MB, Genco CA. Invasion of aortic and heart endothelial cells by Porphyromonas gingivalis. Infect. Immun., 1998, 66: 5337-5343.

[42] Edfeldt K, Swedenborg J, Hansson GK, Yan ZQ. Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation, 2002, 105: 1158-1161.

[43] Naiki Y, . TLR/MyD88 and liver X receptor alpha signaling pathways reciprocally control Chlamydia pneumoniae-induced acceleration of atherosclerosis. J. Immunol., 2008, 181: 7176-7185.

[44] Imler JL, Hoffmann JA. Toll signaling: the TIReless quest for specificity. Nat. Immunol., 2003, 4: 105-106.

[45] Bainbridge BW, Darveau RP. Porphyromonas gingivalis lipopolysaccharide: an unusual pattern recognition receptor ligand for the innate host defense system. Acta Odontol. Scand., 2001, 59: 131-138.

[46] Asai Y, Ohyama Y, Gen K, Ogawa T. Bacterial fimbriae and their peptides activate human gingival epithelial cells through toll-like receptor 2. Infect. Immun., 2001, 69: 7387-7395.

[47] Yumoto H, . Sensitization of human aortic endothelial cells to lipopolysaccharide via regulation of toll-like receptor 4 by bacterial fimbria-dependent invasion. Infect. Immun., 2005, 73: 8050-8059.

[48] Suganami T, . Role of the toll-like receptor 4/NF-kappaB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages. Arterioscler. Thromb. Vasc. Biol., 2007, 27: 84-91.

[49] Hu ZP, . Melatonin ameliorates vascular endothelial dysfunction, inflammation, and atherosclerosis by suppressing the TLR4/NF-kappaB system in high-fat-fed rabbits. J. Pineal Res., 2013, 55: 388-398.

[50] Yang L, . Overexpression of CRY1 protects against the development of atherosclerosis via the TLR/NF-kappaB pathway. Int. Immunopharmacol., 2015, 28: 525-530.

[51] Lockhart PB, . Periodontal disease and atherosclerotic vascular disease: does the evidence support an independent association?: a scientific statement from the American Heart Association. Circulation, 2012, 125: 2520-2544.

Funding

the National Science Foundation for Distinguished Young Scholars of China (31725011); Chinese Stomatological Association (CSA-Z2015-01).

the National Science Foundation for Young Scientists of China (81800986)