Streptococcus pneumoniae infection promotes the long-term development of an atherosclerotic phenotype in atheroprone ApoE-deficient mice

Lisa Peters (Berlin)1, S. Simmons (Berlin)1, L. F. Ginsbach (Berlin)1, P. Ramezani Rad (Berlin)2, V. Nageswaran (Berlin)2, M. Brack (Berlin)3, U. Behrendt (Berlin)3, G. Nouailles (Berlin)3, A. Haghikia (Berlin)2, M. Witzenrath (Berlin)3, W. Kübler (Berlin)4

1Institut für Physiologie, Charité - Universitätsmedizin Berlin Labor für Lungenkreislaufforschung, Nachwuchsgruppe Immunodynamik Berlin, Deutschland; 2Charité - Universitätsmedizin Berlin CC 11: Med. Klinik für Kardiologie Berlin, Deutschland; 3Charité - Universitätsmedizin Berlin Klinik für Pneumologie, Beatmungsmedizin und Intensivmedizin Berlin, Deutschland; 4Charité - Universitätsmedizin Berlin Institut für Physiologie Berlin, Deutschland


Background: Epidemiological studies have identified pneumonia to be closely linked to an increased risk for cardiovascular events. Potential causality of this association, however, remains to be established, and underlying mechanisms are yet to be resolved. Here, we tested the hypothesis that prior pulmonary infection with Streptococcus pneumoniae accelerates the development of an atherosclerotic phenotype in mice. Such a phenotype would explain the increased cardiovascular risk in the epidemiological data. Methods: Atheroprone ApoE-/- mice were fed a high fat diet, and after 6 weeks nasally infected with either 2.5 x 107 S. pneumoniae or vehicle control. Antibiotic therapy was initiated 60h post infection (p.i.) by s.c. injections of ampicillin on 5 consecutive days followed by oral administration of amoxicillin for 10 days. At days 35 or 90 post-infection, aortas were harvested and assessed for vasoreactivity and arterial stiffness by wire myography. Morphological changes of the aortic vessel wall and eNOS expression levels were quantified by western blot and histological stainings. Results: Unexpectedly, 35 days p.i. aortas of infected mice presented with decreased aortic stiffness, increased endothelial-independent vasorelaxation and decreased wall thickness due to lower collagen-1 expression and reduced elastin fragmentation when compared to sham animals. After 90 days, however, these effects had reversed and animals with prior pneumonia showed increased aortic stiffness, attenuated endothelial dependent vasorelaxation that was associated with reduced eNOS protein expression and phosphorylation, and increased atherosclerotic plaque burden relative to vehicle control. Conclusion: Single episodes of pneumonia promote a delayed pro-atherogenic phenotype that manifests as endothelial dysfunction, aortic stiffening and enhanced plaque burden. Underlying mechanisms are currently under investigation to identify risk predictors for patient stratification and clinical targets for prevention of cardiovascular disease following pneumonia.

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