Proliferative stimulation of the vascular endothelin-1 axis in vitro and ex vivo by infection with Chlamydia pneumoniae
Jan Marco Kern
1
Institute of Medical Microbiology, Hygiene and Infectious Diseases, Paracelsus Medical Private University, University Hospital Salzburg, Austria
,
Viola Maass
1
Institute of Medical Microbiology, Hygiene and Infectious Diseases, Paracelsus Medical Private University, University Hospital Salzburg, Austria
,
Jan Rupp
2
Institute of Medical Microbiology and Hygiene, University Hospital Schleswig-Holstein Campus Luebeck, Luebeck, Germany
,
Matthias Maass
1
Institute of Medical Microbiology, Hygiene and Infectious Diseases, Paracelsus Medical Private University, University Hospital Salzburg, Austria
› Author AffiliationsFinancial support: Financial support and grants were received from the Austrian Federal Ministry of Science and Research/GEN-AU: European Initiative to Fight Chlamydial Infections by Unbiased Genomics (ECIBUG) and ChlamyTrans, ERA-Net PathoGenoMics. Fonds zur Förderung der Wissenschaften, Vienna, Austria, grant FWF I126-B09, Deutsche Forschungsgemein-schaft, Bonn, Germany, grant DFG Ma 2070/4–3.
Endothelin-1 (ET-1) is a vasoactive peptide that modifies vascular function via the G-protein coupled transmembrane receptors, Endothelin-A receptor (ETAR) and Endothelin-B receptor (ETBR). Dysregulation of the ET-1 axis plays a role in atherosclerotic development as it triggers cell proliferation, inflammation, and vasoconstriction.The respiratory pathogen Chlamydia pneumoniae (Cp) has been recovered from atherosclerotic lesions, and related to atherogenesis, via activation of vascular small GTPases and leukocyte recruitment. Cp effectively reprograms host cell signalling and is able to enter an intracellular persistent state in vascular cells that is refractory to antibiotics. Upon chlamydial infection, vascular smooth muscle cells, which do not produce significant ET-1 under physiological conditions were switched into a fundamental source of ET-1 mRNA and protein in a p38-MAP-kinase-dependent pathway. Endothelial cells did not overproduce ET-1 but showed upregulation of mitogenic ETAR mRNA and protein while the counterbalancing ETBR, which regulates ET-1 clearance, remained unaffected.This disruption of the ET-1 axis was confirmed in an ex vivo mouse aortic ring model, and resulted in endothelial cell proliferation that could be abrogated by ETAR-siRNA and the selective ETAR-antagonist BQ-123. Chronic chlamydial infection of the vascular wall might represent a permanent noxious stimulus linked to the endothelial cell proliferation characteristic of early atherosclerosis. Suppression of this deleterious paracrine loop by ETAR antagonism opens up a new option of preventing possible vascular sequelae of otherwise untreatable chronic chlamydial infection. In conclusion, this is the first study to demonstrate infection to dysregulate the ET-1 axis towards inducing a proatherogenic proliferative phenotype.
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