Coronary artery disease (CAD) is a major cause of morbidity and mortality worldwide. Recent interest has focused on chronic infectious diseases such as periodontal infection as potential contributors to CAD since traditional risk factors, including hypercholesterolemia, smoking, and hypertension fail to fully explain the incidence of CAD. Epidemiological studies indicate that individuals with periodontal infection are 30 to 100% more likely to have CAD. During the past funding cycle, we generated substantial data related to the role of infection-sensing circuits and ensuing inflammatory cytokine expression in a mouse model of Porphyromonas gingivalis (P.g)-associated atherogenesis. Pertinent to this competing application, we evaluated the role of P.g invasion in atherogenesis. We found that when invasion-deficient P.g. strain DPG3 was substituted for wild-type P.g, or when treatment with the invasion interfering antibiotic metronidazole was included, subsequent atherogenesis was reduced by about 50%, supporting the existence of an invasion-mediated cytosolic process that contributes significantly to P.g-driven atherogenesis. We have also begun to characterize the mechanisms linking infection and atherogenesis. Nucleotide binding oligomerization domain- like receptors (NOD1 and NOD2) represent an immune surveillance system that detects the presence of microbial molecules inside the cell. Recently peptidoglycan (PGN;a TLR2 ligand) was shown to be recognized independently of its muramyl dipeptide (MDP) components (NOD2 ligands) by cell-surface TLR2, and also to activate NF-:B through a distinct TLR signaling pathway involving MyD88. This introduced the possibility that TLR2 and NOD2 signaling are linked, and that one function of NOD2 is the regulation of TLR2. However, the role of NOD2 in TLR-mediated cytokine responses remains controversial. Our preliminary data show that introducing NOD2 siRNA into P.g-stimulated macrophages heightens the pro-inflammatory response. However, NOD2 activation of TLR2-mediated cytokine response was found dependent on MDP dose: low ligand stimulation appears to be synergistic while high ligand levels appear inhibitory. This regulation leads to NF:B modulation and IL-1 and TNF transcriptional regulation. Our hypothesis is that activation of NOD2 negatively regulates TLR2 responses, which in turn reduce artherosclerosis;the absence of such regulation leads to heightened immune responses and aggravated atherosclerosis. To test our hypothesis we are proposing in Aim 1 to use loss of function studies to determine the role of NOD2 in P.g- driven atherosclerosis;
in Aim 2 to determine the molecular mechanisms involved in NOD2 regulation of the innate inflammatory response and invasion-mediated cytosolic process;and in Aim 3 to determine whether administration of muramyl dipeptide (MDP) or NOD2 blockers protect mice from P. g induced atherosclerosis using gain of function studies. These experiments will clearly define the role of NOD2 in P.g atherogenesis and pave the way for pharmacological interventions aimed at reducing or preventing atherogenesis.
Coronary artery disease (CAD) is a major cause of morbidity and mortality in humans worldwide. The results of the proposed experiments will define the role of immune sensing in infection-associated atherogenesis and pave the way for pharmacological interventions aimed reducing or preventing atherogenesis.
|Amar, S; Engelke, M (2015) Periodontal innate immune mechanisms relevant to atherosclerosis. Mol Oral Microbiol 30:171-85|
|Mazumdar, Varun; Snitkin, Evan S; Amar, Salomon et al. (2009) Metabolic network model of a human oral pathogen. J Bacteriol 191:74-90|
|Amar, Salomon; Wu, Shou-chieh; Madan, Monika (2009) Is Porphyromonas gingivalis cell invasion required for atherogenesis? Pharmacotherapeutic implications. J Immunol 182:1584-92|
|Madan, Monika; Amar, Salomon (2008) Toll-like receptor-2 mediates diet and/or pathogen associated atherosclerosis: proteomic findings. PLoS One 3:e3204|
|Lowry, Matthew H; McAllister, Brian P; Jean, Jyh-Chang et al. (2008) Lung lining fluid glutathione attenuates IL-13-induced asthma. Am J Respir Cell Mol Biol 38:509-16|
|Madan, Monika; Bishayi, Biswadev; Hoge, Michael et al. (2008) Atheroprotective role of interleukin-6 in diet- and/or pathogen-associated atherosclerosis using an ApoE heterozygote murine model. Atherosclerosis 197:504-14|
|Madan, Monika; Bishayi, Biswadev; Hoge, Mike et al. (2007) Doxycycline affects diet- and bacteria-associated atherosclerosis in an ApoE heterozygote murine model: cytokine profiling implications. Atherosclerosis 190:62-72|
|Kim, Jemin; Amar, Salomon (2006) Periodontal disease and systemic conditions: a bidirectional relationship. Odontology 94:10-21|
|Leone, Cataldo W; Bokhadhoor, Haneen; Kuo, David et al. (2006) Immunization enhances inflammation and tissue destruction in response to Porphyromonas gingivalis. Infect Immun 74:2286-92|
|Hoge, Mike; Amar, Salomon (2006) Role of interleukin-1 in bacterial atherogenesis. Drugs Today (Barc) 42:683-8|
Showing the most recent 10 out of 12 publications