Hyperlipidemia is necessary for the initiation and progression of atherosclerosis by severe periodontitis in mice

Suh,Jin Sook; Kim,Sharon Y.J.; Lee,Sung Hee; Kim,Reuben H.; Park,No-Hee

doi:10.3892/mmr.2022.12789

Hyperlipidemia is necessary for the initiation and progression of atherosclerosis by severe periodontitis in mice

Authors:
- Jin Sook Suh
- Sharon Y.J. Kim
- Sung Hee Lee
- Reuben H. Kim
- No-Hee Park
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Affiliations: The Shapiro Family Laboratory of Viral Oncology and Aging Research, School of Dentistry, University of California, Los Angeles, CA 90095, USA
Published online on: July 4, 2022 https://doi.org/10.3892/mmr.2022.12789
Article Number: 273
Copyright: © Suh et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hyperlipidemia is a major risk of atherosclerosis; however, systemic inflammatory diseases such as rheumatoid arthritis, psoriasis, systemic lupus erythematosus and systemic sclerosis are also known risks for the development of atherosclerosis. Periodontitis, a local and systemic inflammatory condition, has also been reported as a risk for atherosclerosis, but the specific link between periodontitis and atherosclerosis remains somewhat controversial. We previously reported that ligature‑induced periodontitis exacerbates atherosclerosis in hyperlipidemic Apolipoprotein E‑deficient (ApoE^‑/‑) mice. To understand whether hyperlipidemia is necessary for the development and exacerbation of atherosclerosis associated with periodontitis, the present study created ligature‑induced periodontitis in both wild‑type (WT) and ApoE^‑/‑ mice. Subsequently, the status of local, systemic and vascular inflammation, serum lipid contents and arterial lipid deposition were examined with histological analysis, µCT, en face analysis, serum lipid and cytokine measurements, reverse transcription‑quantitative PCR and immunohistochemical analysis. Ligature placement induced severe periodontitis in both WT and ApoE^‑/‑ mice at the local level as demonstrated by gingival inflammation, alveolar bone loss, increased osteoclastic activities and inflammation in alveolar bone. Systemic inflammation was also induced by ligature placement in both WT and ApoE^‑/‑ mice, albeit more so in ApoE^‑/‑ mice. The serum cholesterol levels were not altered by the ligature in both WT and ApoE^‑/‑ mice. However, the vascular inflammation and arterial lipid deposition were induced by ligature‑induced periodontitis only in ApoE^‑/‑ mice, but not in WT mice. The present study indicated that the coupling of systemic inflammation and hyperlipidemia was necessary for the development and exacerbation of atherosclerosis induced by ligature‑induced periodontitis in mice.

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1	Eke PI, Dye BA, Wei L, Thornton-Evans GO and Genco RJ; CDC Periodontal Disease Surveillance workgroup, : James Beck (University of North Carolina, Chapel Hill, USA), Gordon Douglass (Past President, American Academy of Periodontology), Roy Page (University of Washin: Prevalence of periodontitis in adults in the United States: 2009 and 2010. J Dent Res. 91:914–920. 2012. View Article : Google Scholar : PubMed/NCBI
2	Eke PI, Dye BA, Wei L, Slade GD, Thornton-Evans GO, Borgnakke WS, Taylor GW, Page RC, Beck JD and Genco RJ: Update on prevalence of periodontitis in adults in the United States: NHANES 2009 to 2012. J Periodontol. 86:611–622. 2015. View Article : Google Scholar : PubMed/NCBI
3	Dzink JL, Tanner AC, Haffajee AD and Socransky SS: Gram negative species associated with active destructive periodontal lesions. J Clin Periodontol. 12:648–659. 1985. View Article : Google Scholar : PubMed/NCBI
4	Kinane DF, Zhang P, Benakanakere M, Singleton J, Biesbrock A, Nonnenmacher C and He T: Experimental gingivitis, bacteremia and systemic biomarkers: A randomized clinical trial. J Periodontal Res. 50:864–869. 2015. View Article : Google Scholar : PubMed/NCBI
5	Slots J: Periodontitis: Facts, fallacies and the future. Periodontol. 75:7–23. 2000. View Article : Google Scholar : PubMed/NCBI
6	Rydén L, Buhlin K, Ekstrand E, de Faire U, Gustafsson A, Holmer J, Kjellström B, Lindahl B, Norhammar A, Nygren Å, et al: Periodontitis increases the risk of a first myocardial infarction: A report from the PAROKRANK study. Circulation. 133:576–583. 2016. View Article : Google Scholar : PubMed/NCBI
7	Slocum C, Kramer C and Genco CA: Immune dysregulation mediated by the oral microbiome: Potential link to chronic inflammation and atherosclerosis. J Intern Med. 280:114–128. 2016. View Article : Google Scholar : PubMed/NCBI
8	Jain A, Batista EL Jr, Serhan C, Stahl GL and Van Dyke TE: Role for periodontitis in the progression of lipid deposition in an animal model. Infect Immun. 71:6012–6018. 2003. View Article : Google Scholar : PubMed/NCBI
9	Hasturk H, Abdallah R, Kantarci A, Nguyen D, Giordano N, Hamilton J and Van Dyke TE: Resolvin E1 (RvE1) attenuates atherosclerotic plaque formation in diet and inflammation-induced atherogenesis. Arterioscler Thromb Vasc Biol. 35:1123–1133. 2015. View Article : Google Scholar : PubMed/NCBI
10	Joshi NV, Toor I, Shah AS, Carruthers K, Vesey AT, Alam SR, Sills A, Hoo TY, Melville AJ, Langlands SP, et al: Systemic atherosclerotic inflammation following acute myocardial infarction: Myocardial infarction begets myocardial infarction. J Am Heart Assoc. 4:e0019562015. View Article : Google Scholar : PubMed/NCBI
11	Soehnlein O and Libby P: Targeting inflammation in atherosclerosis-from experimental insights to the clinic. Nat Rev Drug Discov. 20:589–610. 2021. View Article : Google Scholar : PubMed/NCBI
12	Hansson BG, Rosenquist K, Antonsson A, Wennerberg J, Schildt EB, Bladström A and Andersson G: Strong association between infection with human papillomavirus and oral and oropharyngeal squamous cell carcinoma: A population-based case-control study in southern Sweden. Acta Otolaryngol. 125:1337–1344. 2005. View Article : Google Scholar : PubMed/NCBI
13	Libby P, Ridker PM and Hansson GK: Progress and challenges in translating the biology of atherosclerosis. Nature. 473:317–325. 2011. View Article : Google Scholar : PubMed/NCBI
14	Gargiulo P, Marsico F, Parente A, Paolillo S, Cecere M, Casaretti L, Pellegrino AM, Formisano T, Fabiani I, Soricelli A, et al: Ischemic heart disease in systemic inflammatory diseases. An appraisal. Int J Cardiol. 170:286–290. 2014. View Article : Google Scholar : PubMed/NCBI
15	Offenbacher S, Beck JD, Moss K, Mendoza L, Paquette DW, Barrow DA, Couper DJ, Stewart DD, Falkner KL, Graham SP, et al: Results from the Periodontitis and Vascular Events (PAVE) Study: A pilot multicentered, randomized, controlled trial to study effects of periodontal therapy in a secondary prevention model of cardiovascular disease. J Periodontol. 80:190–201. 2009. View Article : Google Scholar : PubMed/NCBI
16	Beck J, Garcia R, Heiss G, Vokonas PS and Offenbacher S: Periodontal disease and cardiovascular disease. J Periodontol. 67 (Suppl 10):S1123–S1137. 1996. View Article : Google Scholar
17	Suh JS, Kim S, Boström KI, Wang CY, Kim RH and Park NH: Periodontitis-induced systemic inflammation exacerbates atherosclerosis partly via endothelial-mesenchymal transition in mice. Int J Oral Sci. 11:212019. View Article : Google Scholar : PubMed/NCBI
18	Oberoi R, Vlacil AK, Schuett J, Schösser F, Schuett H, Tietge UJF, Schieffer B and Grote K: Anti-tumor necrosis factor-α therapy increases plaque burden in a mouse model of experimental atherosclerosis. Atherosclerosis. 277:80–89. 2018. View Article : Google Scholar : PubMed/NCBI
19	Suh JS, Lee SH, Fouladian Z, Lee JY, Kim T, Kang MK, Lusis AJ, Boström KI, Kim RH and Park NH: Rosuvastatin prevents the exacerbation of atherosclerosis in ligature-induced periodontal disease mouse model. Sci Rep. 10:63832020. View Article : Google Scholar : PubMed/NCBI
20	Kim T, Kim S, Song M, Lee C, Yagita H, Williams DW, Sung EC, Hong C, Shin KH, Kang MK, et al: Removal of pre-existing periodontal inflammatory condition before tooth extraction ameliorates medication-related osteonecrosis of the jaw-like lesion in mice. Am J Pathol. 188:2318–2327. 2018. View Article : Google Scholar : PubMed/NCBI
21	Huang Q, Qin L, Dai S, Zhang H, Pasula S, Zhou H, Chen H and Min W: AIP1 suppresses atherosclerosis by limiting hyperlipidemia-induced inflammation and vascular endothelial dysfunction. Arterioscler Thromb Vasc Biol. 33:795–804. 2013. View Article : Google Scholar : PubMed/NCBI
22	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C (T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
23	Lamont RJ, Koo H and Hajishengallis G: The oral microbiota: Dynamic communities and host interactions. Nat Rev Microbiol. 16:745–759. 2018. View Article : Google Scholar : PubMed/NCBI
24	Mussbacher M, Salzmann M, Brostjan C, Hoesel B, Schoergenhofer C, Datler H, Hohensinner P, Basílio J, Petzelbauer P, Assinger A and Schmid JA: Cell type-specific roles of NF-κB linking inflammation and thrombosis. Front Immunol. 10:852019. View Article : Google Scholar : PubMed/NCBI
25	Getz GS and Reardon CA: Animal models of atherosclerosis. Arterioscler Thromb Vasc Biol. 32:1104–1115. 2012. View Article : Google Scholar : PubMed/NCBI
26	Pendse AA, Arbones-Mainar JM, Johnson LA, Altenburg MK and Maeda N: Apolipoprotein E knock-out and knock-in mice: Atherosclerosis, metabolic syndrome, and beyond. J Lipid Res. 50 (Suppl):S178–S182. 2009. View Article : Google Scholar : PubMed/NCBI
27	Mahley RW: Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology. Science. 240:622–630. 1988. View Article : Google Scholar : PubMed/NCBI
28	Machado AC, Quirino MR and Nascimento LF: Relation between chronic periodontal disease and plasmatic levels of triglycerides, total cholesterol and fractions. Braz Oral Res. 19:284–289. 2005. View Article : Google Scholar : PubMed/NCBI
29	Valentaviciene G, Paipaliene P, Nedzelskiene I, Zilinskas J and Anuseviciene OV: The relationship between blood serum lipids and periodontal condition. Stomatologija. 8:96–100. 2006.PubMed/NCBI
30	Thapa S and Wei F: Association between high serum total cholesterol and periodontitis: National Health and nutrition examination survey 2011 to 2012 study of American adults. J Periodontol. 87:1286–1294. 2016. View Article : Google Scholar : PubMed/NCBI
31	Lee S, Im A, Burm E and Ha M: Association between periodontitis and blood lipid levels in a Korean population. J Periodontol. 89:28–35. 2018.PubMed/NCBI
32	IL6R Genetics Consortium Emerging Risk Factors Collaboration, . Sarwar N, Butterworth AS, Freitag DF, Gregson J, Willeit P, Gorman DN, Gao P, Saleheen D, Rendon A, et al: Interleukin-6 receptor pathways in coronary heart disease: A collaborative meta-analysis of 82 studies. Lancet. 379:1205–1213. 2012. View Article : Google Scholar : PubMed/NCBI
33	Mann DL: Innate immunity and the failing heart: The cytokine hypothesis revisited. Circ Res. 116:1254–1268. 2015. View Article : Google Scholar : PubMed/NCBI
34	Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, et al: Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 377:1119–1131. 2017. View Article : Google Scholar : PubMed/NCBI
35	Kozarov EV, Dorn BR, Shelburne CE, Dunn WA Jr and Progulske-Fox A: Human atherosclerotic plaque contains viable invasive Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis. Arterioscler Thromb Vasc Biol. 25:e17–e18. 2005. View Article : Google Scholar : PubMed/NCBI
36	Gibson FC III, Hong C, Chou HH, Yumoto H, Chen J, Lien E, Wong J and Genco CA: Innate immune recognition of invasive bacteria accelerates atherosclerosis in apolipoprotein E-deficient mice. Circulation. 109:2801–2806. 2004. View Article : Google Scholar : PubMed/NCBI
37	Lalla E, Lamster IB, Hofmann MA, Bucciarelli L, Jerud AP, Tucker S, Lu Y, Papapanou PN and Schmidt AM: Oral infection with a periodontal pathogen accelerates early atherosclerosis in apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol. 23:1405–1411. 2003. View Article : Google Scholar : PubMed/NCBI
38	Wigren M, Nilsson J and Kaplan MJ: Pathogenic immunity in systemic lupus erythematosus and atherosclerosis: Common mechanisms and possible targets for intervention. J Intern Med. 278:494–506. 2015. View Article : Google Scholar : PubMed/NCBI
39	Xu S, Pelisek J and Jin ZG: Atherosclerosis is an epigenetic disease. Trends Endocrinol Metab. 29:739–742. 2018. View Article : Google Scholar : PubMed/NCBI
40	Koelwyn GJ, Corr EM, Erbay E and Moore KJ: Regulation of macrophage immunometabolism in atherosclerosis. Nat Immunol. 19:526–537. 2018. View Article : Google Scholar : PubMed/NCBI
41	Daugherty A, Tall AR, Daemen MJAP, Falk E, Fisher EA, García-Cardeña G, Lusis AJ, Owens AP III, Rosenfeld ME, Virmani R, et al: Recommendation on design, execution, and reporting of animal atherosclerosis studies: A scientific statement from the american heart association. Circ Res. 121:e53–e79. 2017. View Article : Google Scholar : PubMed/NCBI
42	Hinder LM, Vincent AM, Hayes JM, McLean LL and Feldman EL: Apolipoprotein E knockout as the basis for mouse models of dyslipidemia-induced neuropathy. Exp Neurol. 239:102–110. 2013. View Article : Google Scholar : PubMed/NCBI