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Modulaton of gene expression in human aortic smooth muscle cells by Porphyromonas gingivalis: a possible association between periodontitis and atherosclerosis
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Modulation of gene expression in human aortic smooth muscle cells by Porphyromonas gingivalis (English)
Abstract [en]

Porphyromonas gingivalis is a gram-negative, rod-shaped, and anaerobic bacterium that is involved in the pathogenesis of periodontitis. P. gingivalis produces a variety of virulence factors including gingipains and fimbriae. These virulence factors not only have a detrimental effect on bacteria adhesion, invasion, and colonization but also affect the host cell inflammatory response. P. gingivalis is also considered to play an role in the development of other diseases, such as atherosclerosis and cancer. Smooth muscle cells are the main components of vascular walls and regulate the width of the blood vessels in the body. To understand the mechanisms underlying the association between periodontitis and atherosclerosis we have, in the studies involved in this thesis, treated human aortic smooth muscle cells (AoSMCs) with wild type, gingipain mutant, and fimbriae mutant strains of P. gingivalis. Using a human whole genome microarray, quanti-tative real time PCR, Western blotting, ELISA, confocal microscopy, and cellular function experiments, we found that P. gingivalis invades AoSMCs, regulates the expression of thousands of genes, and increases cell proliferation by activating the TGFbeta/Notch signaling pathway. The results also show that P. gingivalis increases the ratio of angiopoietin 2 (Angpt2) / angiopoietin 1 (Angpt1) in AoSMCs, which determines the regulatory role of angiopoietins in angiogenesis and their involvement in the development of atherosclerosis. Moreover, we also found that P. gingivalis can induce interleukin-1β (IL-1β) production in AoSMCs, while inhibiting the expression of NLRP3 inflammasome components. Gingipains, especially arginine gingipain, play a fundamental role in P. gingivalis-induced modification of AoSMCs. These findings further support an association between periodontitis and cardiovascular disease.

Place, publisher, year, edition, pages
Örebro: Örebro university , 2015. , 68 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 127
Keyword [en]
Microarray, Angiopoietin, Smooth muscle cells, TNF, Periodontitis, Atherosclerosis, Porphyromonas gingivalis, Cancer, Inflammasome
National Category
Cell and Molecular Biology
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-45835ISBN: 978-91-7529-093-5 (print)OAI: oai:DiVA.org:oru-45835DiVA: diva2:854911
Public defence
2015-11-06, Universitetssjukhuset, hörsal C1, Södra Grev Rosengatan, Örebro, 09:00 (English)
Opponent
Supervisors
Available from: 2015-09-18 Created: 2015-09-18 Last updated: 2015-12-21Bibliographically approved
List of papers
1. The periodontal pathogen Porphyromonas gingivalis changes the gene expression in vascular smooth muscle cells involving the TGFbeta/Notch signalling pathway and increased cell proliferation
Open this publication in new window or tab >>The periodontal pathogen Porphyromonas gingivalis changes the gene expression in vascular smooth muscle cells involving the TGFbeta/Notch signalling pathway and increased cell proliferation
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2013 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, 770- p.Article in journal (Refereed) Published
Abstract [en]

Background: Porphyromonas gingivalis is a gram-negative bacterium that causes destructive chronic periodontitis. In addition, this bacterium is also involved in the development of cardiovascular disease. The aim of this study was to investigate the effects of P. gingivalis infection on gene and protein expression in human aortic smooth muscle cells (AoSMCs) and its relation to cellular function.

Results: AoSMCs were exposed to viable P. gingivalis for 24 h, whereafter confocal fluorescence microscopy was used to study P. gingivalis invasion of AoSMCs. AoSMCs proliferation was evaluated by neutral red assay. Human genome microarray, western blot and ELISA were used to investigate how P. gingivalis changes the gene and protein expression of AoSMCs. We found that viable P. gingivalis invades AoSMCs, disrupts stress fiber structures and significantly increases cell proliferation. Microarray results showed that, a total of 982 genes were identified as differentially expressed with the threshold log2 fold change >|1| (adjust p-value <0.05). Using bioinformatic data mining, we demonstrated that up-regulated genes are enriched in gene ontology function of positive control of cell proliferation and down-regulated genes are enriched in the function of negative control of cell proliferation. The results from pathway analysis revealed that all the genes belonging to these two categories induced by P. gingivalis were enriched in 25 pathways, including genes of Notch and TGF-beta pathways.

Conclusions: This study demonstrates that P. gingivalis is able to invade AoSMCs and stimulate their proliferation. The activation of TGF-beta and Notch signaling pathways may be involved in the bacteria-mediated proliferation of AoSMCs. These findings further support the association between periodontitis and cardiovascular diseases.

Keyword
Porphyromonas gingivalis, Aortic smooth muscle cells, Proliferation, Gene expression profiling
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:oru:diva-33287 (URN)10.1186/1471-2164-14-770 (DOI)000328639800002 ()24209892 (PubMedID)2-s2.0-84887327838 (Scopus ID)
Funder
Swedish Research Council, 2008-2459Swedish Heart Lung Foundation, 2011-0632
Note

Funding Agency: Foundation of Olle Engkvist; Foundation of Mats Kleberg (se även Forskningsfinansiär)

Available from: 2014-01-24 Created: 2014-01-24 Last updated: 2015-10-16Bibliographically approved
2. Gingipains from the Periodontal Pathogen Porphyromonas gingivalis Play a Significant Role in Regulation of Angiopoietin 1 and Angiopoietin 2 in Human Aortic Smooth Muscle Cells
Open this publication in new window or tab >>Gingipains from the Periodontal Pathogen Porphyromonas gingivalis Play a Significant Role in Regulation of Angiopoietin 1 and Angiopoietin 2 in Human Aortic Smooth Muscle Cells
2015 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 83, no 11, 4256-4265 p.Article in journal (Refereed) Published
Abstract [en]

Angiopoietin 1 (Angpt1) and angiopoietin 2 (Angpt2) are the ligands of tyrosine kinase (Tie) receptors, and they play important roles in vessel formation and the development of inflammatory diseases, such as atherosclerosis. Porphyromonas gingivalis is a Gram-negative periodontal bacterium that is thought to contribute to the progression of cardiovascular disease. The aim of this study was to investigate the role of P. gingivalis infection in the modulation of Angpt1 and Angpt2 in human aortic smooth muscle cells (AoSMCs). We exposed AoSMCs to wild-type (W50 and 381), gingipain mutant (E8 and K1A), and fimbrial mutant (DPG-3 and KRX-178) P. gingivalis strains and to different concentrations of tumor necrosis factor (TNF). The atherosclerosis risk factor TNF was used as a positive control in this study. We found that P. gingivalis (wild type, K1A, DPG3, and KRX178) and TNF upregulated the expression of Angpt2 and its transcription factor ETS1, respectively, in AoSMCs. In contrast, Angpt1 was inhibited by P. gingivalis and TNF. However, the RgpAB mutant E8 had no effect on the expression of Angpt1, Angpt2, or ETS1 in AoSMCs. The results also showed that ETS1 is critical for P. gingivalis induction of Angpt2. Exposure to Angpt2 protein enhanced the migration of AoSMCs but had no effect on proliferation. This study demonstrates that gingipains are crucial to the ability of P. gingivalis to markedly increase the expressed Angpt2/Angpt1 ratio in AoSMCs, which determines the regulatory role of angiopoietins in angiogenesis and their involvement in the development of atherosclerosis. These findings further support the association between periodontitis and cardiovascular disease.

Place, publisher, year, edition, pages
American Society for Microbiology, 2015
Keyword
Angiopoietin 1, Angiopoietin 2, Smooth Muscle cells, TNF, Periodontitis, Atherosclerosis, Porphyromonas gingivalis
National Category
Cell and Molecular Biology Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:oru:diva-46137 (URN)10.1128/IAI.00498-15 (DOI)000362494000009 ()26283334 (PubMedID)
Funder
Knowledge FoundationSwedish Heart Lung Foundation, T77414
Note

Funding Agencies:

Swedish Research Council for Medicine and Health 2008-2459

Foundation of Olle Engkvist

Foundation of Mats Kleberg

Available from: 2015-10-16 Created: 2015-10-16 Last updated: 2015-11-04Bibliographically approved
3. Transcriptional profiling of human smooth muscle cells infected with gingipain and fimbriae mutants of Porphyromonas gingivalis
Open this publication in new window or tab >>Transcriptional profiling of human smooth muscle cells infected with gingipain and fimbriae mutants of Porphyromonas gingivalis
(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:oru:diva-46139 (URN)
Available from: 2015-10-16 Created: 2015-10-16 Last updated: 2015-10-16Bibliographically approved
4. Poryphyromonas gingivalis induces IL-1β in aortic smooth muscle cells: possible role of gingipains?
Open this publication in new window or tab >>Poryphyromonas gingivalis induces IL-1β in aortic smooth muscle cells: possible role of gingipains?
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(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:oru:diva-46140 (URN)
Available from: 2015-10-16 Created: 2015-10-16 Last updated: 2016-12-08Bibliographically approved

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