Department of Medicine, Division of Cardiovascular Medicine
Animals; Aorta; Apolipoproteins E; Chlamydophila pneumoniae; Diet, Western; *Gene Expression Profiling; Kinetics; Male; Mice; Mice, Inbred C57BL; Multigene Family; Plaque, Atherosclerotic; Porphyromonas gingivalis
Cardiology | Cardiovascular Diseases | Genomics | Pathogenic Microbiology
BACKGROUND: Atherosclerosis is a progressive disease characterized by inflammation and accumulation of lipids in vascular tissue. Porphyromonas gingivalis (Pg) and Chlamydia pneumoniae (Cp) are associated with inflammatory atherosclerosis in humans. Similar to endogenous mediators arising from excessive dietary lipids, these Gram-negative pathogens are pro-atherogenic in animal models, although the specific inflammatory/atherogenic pathways induced by these stimuli are not well defined. In this study, we identified gene expression profiles that characterize P. gingivalis, C. pneumoniae, and Western diet (WD) at acute and chronic time points in aortas of Apolipoprotein E (ApoE-/-) mice.
RESULTS: At the chronic time point, we observed that P. gingivalis was associated with a high number of unique differentially expressed genes compared to C. pneumoniae or WD. For the top 500 differentially expressed genes unique to each group, we observed a high percentage (76%) that exhibited decreased expression in P. gingivalis-treated mice in contrast to a high percentage (96%) that exhibited increased expression in WD mice. C. pneumoniae treatment resulted in approximately equal numbers of genes that exhibited increased and decreased expression. Gene Set Enrichment Analysis (GSEA) revealed distinct stimuli-associated phenotypes, including decreased expression of mitochondrion, glucose metabolism, and PPAR pathways in response to P. gingivalis but increased expression of mitochondrion, lipid metabolism, carbohydrate and amino acid metabolism, and PPAR pathways in response to C. pneumoniae; WD was associated with increased expression of immune and inflammatory pathways. DAVID analysis of gene clusters identified by two-way ANOVA at acute and chronic time points revealed a set of core genes that exhibited altered expression during the natural progression of atherosclerosis in ApoE-/- mice; these changes were enhanced in P. gingivalis-treated mice but attenuated in C. pneumoniae-treated mice. Notable differences in the expression of genes associated with unstable plaques were also observed among the three pro-atherogenic stimuli.
CONCLUSIONS: Despite the common outcome of P. gingivalis, C. pneumoniae, and WD on the induction of vascular inflammation and atherosclerosis, distinct gene signatures and pathways unique to each pro-atherogenic stimulus were identified. Our results suggest that pathogen exposure results in dysregulated cellular responses that may impact plaque progression and regression pathways.
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DOI of Published Version
BMC Genomics. 2014 Dec 24;15:1176. doi: 10.1186/1471-2164-15-1176. Link to article on publisher's site
Kramer, Carolyn D.; Weinberg, Ellen O.; Gower, Adam C.; He, Xianbao; Mekasha, Samrawit; Slocum, Connie; Beaulieu, Lea M.; Wetzler, Lee; Alekseyev, Yuriy; Gibson, Frank C. III; Freedman, Jane E.; Ingalls, Robin R.; and Genco, Caroline A., "Distinct gene signatures in aortic tissue from ApoE-/- mice exposed to pathogens or Western diet" (2014). Open Access Articles. 2566.
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