RESUMO
Altered microRNA expression is implicated in cardiovascular diseases. Our objective was to determine microRNA signatures in thoracic aortic aneurysms (TAAs) and abdominal aortic aneurysms (AAAs) compared with control non-aneurysmal aortic specimens. We evaluated the expression of fifteen selected microRNA in human TAA and AAA operative specimens compared to controls. We observed significant upregulation of miR-221 and downregulation of miR-1 and -133 in TAA specimens. In contrast, upregulation of miR-146a and downregulation of miR-145 and -331-3p were found only for AAA specimens. Upregulation of miR-126 and -486-5p and downregulation of miR-30c-2*, -155, and -204 were observed in specimens of TAAs and AAAs. The data reveal microRNA expression signatures unique to aneurysm location and common to both thoracic and abdominal pathologies. Thus, changes in miR-1, -29a, -133a, and -221 are involved in TAAs and miR-145, -146, and -331-3p impact AAAs. This work validates prior studies on microRNA expression in aneurysmal diseases.
Assuntos
Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Torácica/genética , Predisposição Genética para Doença , MicroRNAs/genética , Idoso , Aneurisma da Aorta Abdominal/diagnóstico , Aneurisma da Aorta Torácica/diagnóstico , Estudos de Casos e Controles , Análise por Conglomerados , Biologia Computacional/métodos , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , TranscriptomaRESUMO
The American Heart Association supports an association between periodontal diseases and atherosclerosis but not a causal association. This study explores the use of the integrin ß6(-/-) mouse model to study the causality. We investigated the ability of a polymicrobial consortium of Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Fusobacterium nucleatum to colonize the periodontium and induce local and systemic inflammatory responses. Polymicrobially infected Itgß6(-/-) mice demonstrate greater susceptibility to gingival colonization/infection, with severe gingival inflammation, apical migration of the junctional epithelium, periodontal pocket formation, alveolar bone resorption, osteoclast activation, bacterial invasion of the gingiva, a greater propensity for the bacteria to disseminate hematogenously, and a strong splenic T cell cytokine response. Levels of atherosclerosis risk factors, including serum nitric oxide, oxidized low-density lipoprotein, serum amyloid A, and lipid peroxidation, were significantly altered by polybacterial infection, demonstrating an enhanced potential for atherosclerotic plaque progression. Aortic gene expression revealed significant alterations in specific Toll-like receptor (TLR) and nucleotide-binding domain- and leucine-rich-repeat-containing receptor (NLR) pathway genes in response to periodontal bacterial infection. Histomorphometry of the aorta demonstrated larger atherosclerotic plaques in Itgß6(-/-) mice than in wild-type (WT) mice but no significant difference in atherosclerotic plaque size between mice with polybacterial infection and mice with sham infection. Fluorescence in situ hybridization demonstrated active invasion of the aortic adventitial layer by P. gingivalis. Our observations suggest that polybacterial infection elicits distinct aortic TLR and inflammasome signaling and significantly increases local aortic oxidative stress. These results are the first to demonstrate the mechanism of the host aortic inflammatory response induced by polymicrobial infection with well-characterized periodontal pathogens.
Assuntos
Túnica Adventícia/patologia , Antígenos de Neoplasias/imunologia , Aorta/patologia , Aterosclerose/complicações , Integrinas/imunologia , Periodontite/complicações , Placa Aterosclerótica/complicações , Túnica Adventícia/imunologia , Túnica Adventícia/microbiologia , Animais , Antígenos de Neoplasias/genética , Aorta/imunologia , Aorta/microbiologia , Aterosclerose/imunologia , Aterosclerose/microbiologia , Aterosclerose/patologia , Bacteroidetes/crescimento & desenvolvimento , Bacteroidetes/imunologia , Bacteroidetes/patogenicidade , Reabsorção Óssea , Modelos Animais de Doenças , Fusobacterium nucleatum/crescimento & desenvolvimento , Fusobacterium nucleatum/imunologia , Fusobacterium nucleatum/patogenicidade , Expressão Gênica , Gengiva/imunologia , Gengiva/microbiologia , Gengiva/patologia , Hibridização in Situ Fluorescente , Inflamassomos , Integrinas/deficiência , Integrinas/genética , Lipoproteínas LDL/genética , Lipoproteínas LDL/imunologia , Camundongos , Camundongos Knockout , Consórcios Microbianos , Periodontite/imunologia , Periodontite/microbiologia , Periodontite/patologia , Periodonto/imunologia , Periodonto/microbiologia , Periodonto/patologia , Placa Aterosclerótica/imunologia , Placa Aterosclerótica/microbiologia , Placa Aterosclerótica/patologia , Porphyromonas gingivalis/crescimento & desenvolvimento , Porphyromonas gingivalis/imunologia , Porphyromonas gingivalis/patogenicidade , Treponema denticola/crescimento & desenvolvimento , Treponema denticola/imunologia , Treponema denticola/patogenicidadeRESUMO
Periodontal disease (PD) and atherosclerotic vascular disease (ASVD) are both chronic inflammatory diseases with a polymicrobial etiology and have been epidemiologically associated. The purpose is to examine whether periodontal bacteria that infect the periodontium can also infect vascular tissues and enhance pre-existing early aortic atherosclerotic lesions in LDLRnull mice. Mice were orally infected with intermediate bacterial colonizer Fusobacterium nucleatum for the first 12 weeks followed by late bacterial colonizers (Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia) for the remaining 12 weeks mimicking the human oral microbiota ecological colonization. Genomic DNA from all four bacterial was detected in gingival plaque by PCR, consistently demonstrating infection of mouse gingival surfaces. Infected mice had significant levels of IgG and IgM antibodies, alveolar bone resorption, and showed apical migration of junctional epithelium revealing the induction of PD. These results support the ability of oral bacteria to cause PD in mice. Detection of bacterial genomic DNA in systemic organs indicates hematogenous dissemination from the gingival pockets. Bacterial infection did not alter serum lipid fractions or serum amyloid A levels and did not induce aortic atherosclerotic plaque. This is the first study examining the causal role of periodontal bacteria in induction of ASVD in LDLRnull mice.
Assuntos
Aterosclerose/genética , Aterosclerose/microbiologia , Interações Hospedeiro-Patógeno , Doenças Periodontais/genética , Doenças Periodontais/microbiologia , Receptores de LDL/deficiência , Perda do Osso Alveolar/etiologia , Perda do Osso Alveolar/patologia , Animais , Anticorpos Antibacterianos/imunologia , Aterosclerose/patologia , Infecções Bacterianas/genética , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Infecções Bacterianas/patologia , Placa Dentária/microbiologia , Placa Dentária/patologia , Gengiva/metabolismo , Gengiva/microbiologia , Gengiva/patologia , Lipídeos/sangue , Masculino , Camundongos , Camundongos Knockout , Doenças Periodontais/patologia , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologiaRESUMO
BACKGROUND: It has been previously hypothesized that oral microbes may be an etiological link between rheumatoid arthritis (RA) and periodontal disease. However, the mechanistic basis of this association is incompletely understood. Here, we investigated the role of periodontal bacteria in induction of joint inflammation in collagen-induced arthritis (CIA) in B10.RIII mice. METHODS: CIA-prone B10.RIII mice were infected orally with a polybacterial mixture of Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia for 24 weeks before induction of CIA. The ability of polybacterial mixture to colonize the periodontium and induce systemic response, horizontal alveolar bone resorption in infected B10.RIII mice was investigated. Arthritis incidence, severity of joint inflammation, pannus formation, skeletal damage, hematogenous dissemination of the infection, matrix metalloproteinase 3 (MMP3) levels, and interleukin-17 expression levels were evaluated. RESULTS: B10.RIII mice had gingival colonization with all three bacteria, higher levels of anti-bacterial immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies, significant alveolar bone resorption, and hematogenous dissemination of P. gingivalis to synovial joints. Infected B10.RIII mice had more severe arthritis, and higher serum matrix metalloproteinase 3 levels and activity. Histopathological analysis showed increased inflammatory cell infiltration, destruction of articular cartilage, erosions, and pannus formation. Additionally, involved joints showed had expression levels of interleukin-17. CONCLUSION: These findings demonstrate that physical presence of periodontal bacteria in synovial joints of B10.RIII mice with collagen-induced arthritis is associated with arthritis exacerbation, and support the hypothesis that oral bacteria, specifically P. gingivalis, play a significant role in augmenting autoimmune arthritis due to their intravascular dissemination to the joints.
Assuntos
Artrite Experimental/microbiologia , Artrite Experimental/patologia , Periodontite/complicações , Membrana Sinovial/microbiologia , Animais , Camundongos , Periodontite/microbiologia , Periodonto/microbiologiaRESUMO
Tannerella forsythia is a Gram-negative anaerobic organism that inhabits the subgingival cavity and initiates connective tissue destruction and alveolar bone resorption in periodontal disease (PD). PD is a chronic immunoinflammatory disease and has been linked to several systemic diseases including atherosclerosis. This study evaluated the effects of a chronic oral infection with T. forsythia ATCC 43037 on the induction of PD, inflammatory markers and atherosclerosis risk factors in hyperlipidemic ApoE(null) mice. Mice were orally infected for 12 and 24 weeks prior to euthanasia. Bacterial colonization of the oral cavity and bacteremia was confirmed via isolation of genomic DNA from oral plaque and tissues. Oral infection elicited significantly elevated levels of serum IgG and IgM antibodies and alveolar bone resorption compared to control mice. Tannerella forsythia-infected mice had increased serum amyloid A, and significantly reduced serum nitric oxide when compared to controls. Tannerella forsythia chronic infection also significantly increased serum lipoproteins suggesting altered cholesterol metabolism and potential for aortic inflammation. Despite enhanced acute phase reactants and altered lipid profiles, T. forsythia infection was associated with decreased aortic plaque. This study investigates the potential of a known periodontal bacterial pathogen found in atherosclerotic plaque in humans to accelerate atherosclerosis in hyperlipdemic mice.
Assuntos
Aterosclerose/microbiologia , Bacteroidetes/imunologia , Infecções por Bactérias Gram-Negativas/complicações , Infecções por Bactérias Gram-Negativas/patologia , Inflamação/microbiologia , Doenças Periodontais/complicações , Doenças Periodontais/patologia , Perda do Osso Alveolar/etiologia , Perda do Osso Alveolar/patologia , Animais , Anticorpos Antibacterianos/sangue , Aterosclerose/patologia , Bacteriemia/microbiologia , Doença Crônica , Infecções por Bactérias Gram-Negativas/imunologia , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Inflamação/patologia , Lipoproteínas/sangue , Masculino , Camundongos , Camundongos Knockout , Óxido Nítrico/sangue , Doenças Periodontais/imunologia , Fatores de Risco , Proteína Amiloide A Sérica/análiseRESUMO
Periodontal disease (PD) develops from a synergy of complex subgingival oral microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). To investigate how a polybacterial microbiome infection influences atherosclerotic plaque progression, we infected the oral cavity of ApoE null mice with a polybacterial consortium of 4 well-characterized periodontal pathogens, Porphyromonas gingivalis, Treponema denticola, Tannerealla forsythia and Fusobacterium nucleatum, that have been identified in human atherosclerotic plaque by DNA screening. We assessed periodontal disease characteristics, hematogenous dissemination of bacteria, peripheral T cell response, serum inflammatory cytokines, atherosclerosis risk factors, atherosclerotic plaque development, and alteration of aortic gene expression. Polybacterial infections have established gingival colonization in ApoE null hyperlipidemic mice and displayed invasive characteristics with hematogenous dissemination into cardiovascular tissues such as the heart and aorta. Polybacterial infection induced significantly higher levels of serum risk factors oxidized LDL (p < 0.05), nitric oxide (p < 0.01), altered lipid profiles (cholesterol, triglycerides, Chylomicrons, VLDL) (p < 0.05) as well as accelerated aortic plaque formation in ApoE null mice (p < 0.05). Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis. Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES. In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNγ, IL-1ß, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules. This study demonstrates unique differences in the host immune response to a polybacterial periodontal infection with atherosclerotic lesion progression in a mouse model.
Assuntos
Periodontite Agressiva/microbiologia , Apolipoproteínas E/genética , Aterosclerose/etiologia , Microbiota , Periodontite Agressiva/complicações , Animais , Quimiocinas/genética , Quimiocinas/metabolismo , Fusobacterium nucleatum/isolamento & purificação , Inflamação/etiologia , Interleucinas/genética , Interleucinas/metabolismo , Masculino , Camundongos , Boca/microbiologia , Porphyromonas gingivalis/isolamento & purificação , Linfócitos T/metabolismo , Treponema denticola/isolamento & purificaçãoRESUMO
The American Heart Association supports an association between periodontal disease (PD) and atherosclerotic vascular disease (ASVD) but does not as of yet support a causal relationship. Recently, we have shown that major periodontal pathogens Porphyromonas gingivalis and Treponema denticola are causally associated with acceleration of aortic atherosclerosis in ApoEnull hyperlipidemic mice. The aim of this study was to determine if oral infection with another significant periodontal pathogen Fusobacterium nucleatum can accelerate aortic inflammation and atherosclerosis in the aortic artery of ApoEnull mice. ApoEnull mice (n = 23) were orally infected with F. nucleatum ATCC 49256 and euthanized at 12 and 24 weeks. Periodontal disease assessments including F. nucleatum oral colonization, gingival inflammation, immune response, intrabony defects, and alveolar bone resorption were evaluated. Systemic organs were evaluated for infection, aortic sections were examined for atherosclerosis, and inflammatory markers were measured. Chronic oral infection established F. nucleatum colonization in the oral cavity, induced significant humoral IgG (P=0.0001) and IgM (P=0.001) antibody response (12 and 24 weeks), and resulted in significant (P=0.0001) alveolar bone resorption and intrabony defects. F. nucleatum genomic DNA was detected in systemic organs (heart, aorta, liver, kidney, lung) indicating bacteremia. Aortic atherosclerotic plaque area was measured and showed a local inflammatory infiltrate revealed the presence of F4/80+ macrophages and CD3+ T cells. Vascular inflammation was detected by enhanced systemic cytokines (CD30L, IL-4, IL-12), oxidized LDL and serum amyloid A, as well as altered serum lipid profile (cholesterol, triglycerides, chylomicrons, VLDL, LDL, HDL), in infected mice and altered aortic gene expression in infected mice. Despite evidence for systemic infection in several organs and modulation of known atherosclerosis risk factors, aortic atherosclerotic lesions were significantly reduced after F. nucleatum infection suggesting a potential protective function for this member of the oral microbiota.
Assuntos
Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Fusobacterium nucleatum/fisiologia , Deleção de Genes , Placa Aterosclerótica/imunologia , Placa Aterosclerótica/microbiologia , Animais , Aorta/patologia , Biomarcadores/metabolismo , Citocinas/metabolismo , Progressão da Doença , Doenças da Gengiva/microbiologia , Imunidade Humoral , Inflamação/metabolismo , Masculino , Camundongos , Boca/microbiologia , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Fatores de RiscoRESUMO
BACKGROUND: Periodontitis is a chronic, polymicrobial inflammatory disease that degrades connective tissue and alveolar bone and results in tooth loss. Oxidative stress has been linked to the onset of periodontal tissue breakdown and systemic inflammation, and the success of antiresorptive treatments will rely on how effectively they can ameliorate periodontal disease-induced oxidative stress during oral infection. METHODS: Rats were infected with polybacterial inoculum consisting of Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, as an oral lavage every other week for 12 weeks. Daily subcutaneous injections of enoxacin, bis-enoxacin, alendronate, or doxycycline were administered for 6 weeks after 6 weeks of polybacterial infection in rats. The serum levels of oxidative stress parameters and antioxidant enzymes, including glutathione peroxidase, superoxide dismutase, and catalase, were evaluated in each of the infected, treated, and sham-infected rats. RESULTS: Rats infected with the periodontal pathogens displayed a five-fold increase in the oxidative stress index compared with controls as a result of increased levels of serum oxidants and decreases in total antioxidant activity. The overall decrease in antioxidant activity occurred despite increases in three important antioxidant enzymes, suggesting an imbalance between antioxidant macromolecules/small molecules production and antioxidant enzyme levels. Surprisingly, the bone-targeted antiresorptives bis-enoxacin and alendronate inhibited increases in oxidative stress caused by periodontitis. Bis-enoxacin, which has both antiresorptive and antibiotic activities, was more effective than alendronate, which acts only as an antiresorptive. CONCLUSION: To the best of the authors' knowledge, this is the first study to demonstrate that the increased oxidative stress induced by periodontal infection in rats can be ameliorated by bone-targeted antiresorptives.