Perturbation of endothelial junction proteins by Staphylococcus aureus alpha-toxin: inhibition of endothelial gap formation by adrenomedullin.
Endothelial hyperpermeability is a hallmark of an inflammatory reaction and contributes to tissue damage in severe infections. Loss of endothelial cell-cell adhesion leads to intercellular gap formation allowing paracellular fluid flux. Although Staphylococcus aureus alpha-toxin significantly contributed to staphylococci disease, little is known about its mechanism of endothelial hyperpermeability induction. Here, we demonstrate that in a model of isolated perfused rat ileum discontinuation of capillary vascular-endothelial-cadherin (VE-cadherin) was observed after bolus application of S. aureus alpha-toxin being inhibited by the endogenous peptide adrenomedullin (ADM). In vitro, alpha-toxin exposure induced loss of immunoreactivity of VE-cadherin and occludin in human cultured umbilical vein endothelial cells. Likewise, ADM blocked alpha-toxin-related junctional protein disappearance from intercellular sites. Additionally, cyclic AMP elevation was shown to stabilize endothelial barrier function after alpha-toxin application. Although no RhoA activation was noted after endothelial alpha-toxin exposure, inhibition of Rho kinase and myosin light chain kinase blocked loss of immunoreactivity of VE-cadherin and occludin as well as intercellular gap formation. In summary, stabilization of endothelial junctional integrity as indicated by interendothelial immunostaining might be an interesting approach to stabilize endothelial barrier function in severe S. aureus infections.
Hocke
Andreas C
AC
Department of Internal Medicine/Infectious and Pulmonary Diseases, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
Temmesfeld-Wollbrueck
Bettina
B
Schmeck
Bernd
B
Berger
Katharina
K
Frisch
Eckehard M
EM
Witzenrath
Martin
M
Brell
Bernhard
B
Suttorp
Norbert
N
Hippenstiel
Stefan
S
D053607:Adrenomedullin / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001427:Bacterial Toxins / Q000493:pharmacokinetics*; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004347:Drug Interactions; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism*; D006460:Hemolysin Proteins / Q000493:pharmacokinetics*; D007082:Ileum / Q000098:blood supply* / Q000187:drug effects; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D007365:Intercellular Junctions / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000494:pharmacology; D018994:Myosin Light Chains / Q000378:metabolism; D062793:Occludin; D017346:Protein Serine-Threonine Kinases; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000008:administration & dosage*; D054460:rho-Associated Kinases; D000099152:Cadherin 5
D053607:Adrenomedullin; D015703:Antigens, CD; D001427:Bacterial Toxins; D015820:Cadherins; D000242:Cyclic AMP; D006460:Hemolysin Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018994:Myosin Light Chains; D062793:Occludin; D017346:Protein Serine-Threonine Kinases; D014665:Vasodilator Agents; D054460:rho-Associated Kinases; D000099152:Cadherin 5; C568985:OCLN protein, human; C568987:Ocln protein, rat; C021091:staphylococcal alpha-toxin