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The periodontal pathogen Porphyromonas gingivalis changes the gene expression in vascular smooth muscle cells involving the TGFbeta/Notch signalling pathway and increased cell proliferation
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.ORCID iD: 0000-0002-3373-7864
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
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2013 (English)In: BMC Genomics, E-ISSN 1471-2164, Vol. 14, p. 770-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.

Place, publisher, year, edition, pages
2013. Vol. 14, p. 770-
Keywords [en]
Porphyromonas gingivalis, Aortic smooth muscle cells, Proliferation, Gene expression profiling
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:oru:diva-33287DOI: 10.1186/1471-2164-14-770ISI: 000328639800002PubMedID: 24209892Scopus ID: 2-s2.0-84887327838OAI: oai:DiVA.org:oru-33287DiVA, id: diva2:690770
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: 2024-01-17Bibliographically approved
In thesis
1. Molecular mechanisms mediating development of pulmonary cachexia in COPD
Open this publication in new window or tab >>Molecular mechanisms mediating development of pulmonary cachexia in COPD
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cigarette smoking (CS) represents the main causative agent underlying development and progress of COPD. Recently, involvement of CS in the pathogenesis of COPDassociated muscle abnormalities is becoming increasingly evident. Nevertheless, involved triggers and underlying mechanisms remain largely unknown. This study was conceived in order to examine effects of cigarette smoke exposure on skeletal muscle morphology, vascular supply and function. For this purpose, we have specifically designed murine COPD/emphysema model and gastrocnemius muscle was examined, while in vitro experiments were conducted using murine C2C12 skeletal muscle myocytes.

In addition to the mild emphysematous changes present in the lungs of CS-exposed mice, our results demonstrated evident signs of muscle atrophy reflected by decreased fiber cross-sectional area, profound fiber size variation and reduced body mass. Furthermore, we have observed impairment in terminal myogenesis and lower number of myonuclei in skeletal muscles of CS-exposed animals despite evident activation of muscle repair process. Additionally, our results demonstrate capillary rarefaction in skeletal muscles of CS-exposed animals which was associated with deregulation of hypoxia-angiogenesis signaling, reduced levels of angiogenic factors such as HIF1-α and VEGF and enhanced expression of VHL and its partner proteins PHD2 and Ube2D1. The results of our in-vitro experiments demonstrated that VHL and its ubiquitination machinery can be synergistically regulated by TNF and hypoxia consequentially impairing angiogenic potential of skeletal muscle myocytes. Finally, we have shown that CS elicits chronic ER stress in murine skeletal muscles which is associated with activation of ERAD and apoptotic pathways as mirrored by elevated expression of Usp19, caspase 12 and caspase 3 in skeletal muscles of CSexposed animals. Moreover, molecular and morphological alterations in CS-exposed mice resulted in impairment of muscle function as reflected by their impaired exercise capacity.

Taken together, from our results it is evident that cigarette smoke exposure elicits set of morphological, vascular and functional changes highly resembling those observed in COPD. Additionally, CS induces wide range of molecular alterations and signaling pathway deregulations suggesting profound effects of cigarette smoke exposure on skeletal muscle cell homeostasis.

Place, publisher, year, edition, pages
Örebro: Örebro university, 2014. p. 76
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 107
Keywords
COPD, cachexia, atrophy, cigarette smoke, myogenesis, angiogenesis
National Category
Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biomedicine; Biochemistry
Identifiers
urn:nbn:se:oru:diva-36104 (URN)978-91-7529-031-7 (ISBN)
Public defence
2014-09-16, Universitetssjukhuset, hörsal C2, Södra Grev Rosengatan, Örebro, 09:15 (English)
Opponent
Available from: 2014-08-25 Created: 2014-08-25 Last updated: 2018-01-11Bibliographically approved
2. Modulaton of gene expression in human aortic smooth muscle cells by Porphyromonas gingivalis: a possible association between periodontitis and atherosclerosis
Open this publication in new window or tab >>Modulaton of gene expression in human aortic smooth muscle cells by Porphyromonas gingivalis: a possible association between periodontitis and atherosclerosis
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[en]
Modulation of gene expression in human aortic smooth muscle cells by Porphyromonas gingivalis
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. p. 68
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 127
Keywords
Microarray, Angiopoietin, Smooth muscle cells, TNF, Periodontitis, Atherosclerosis, Porphyromonas gingivalis, Cancer, Inflammasome
National Category
Cell and Molecular Biology
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-45835 (URN)978-91-7529-093-5 (ISBN)
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: 2024-01-03Bibliographically approved

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Zhang, BoxiElmabsout, Ali AteiaKhalaf, HazemBasic, Vladimir T.Jayaprakash, KartheyaeneKruse, RobertBengtsson, TorbjörnSirsjö, Allan

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School of Health and Medical Sciences, Örebro University, SwedenSchool of Medicine, Örebro University, Sweden
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