title: Angiopoietin-2 is a potential mediator of endothelial barrier dysfunction following cardiopulmonary bypass.
abstract: BACKGROUND
  Endothelial activation leading to vascular barrier dysfunction and organ failure is a well-recognized complication of cardiovascular surgery with cardiopulmonary bypass (CPB). The endothelial-specific angiopoietin-Tie2 ligand-receptor system has been identified as a non-redundant regulator of endothelial activation. Binding of angiopoietin-2 (Ang-2) to the Tie2 receptor antagonizes Tie2 signaling and renders the endothelial barrier responsive to pro-inflammatory cytokines. We aimed to study the time course and potential triggering factors of Ang-2 release after CPB, as well as the association of Ang-2 changes with surrogates of increased vascular permeability, organ dysfunction, and outcome.
  
  
  METHODS
  Serum levels of Ang-2 from 25 adult patients (140 screened) were measured before and at 0, 12, and 24h following CPB procedure by in-house immuno-luminometric assay (ILMA), and compared with indices of organ dysfunction, duration of mechanical ventilation (MV), length of stay (LOS) in the intensive care unit (ICU), and hospital mortality. The effect of Ang-2 was studied in vitro by incubating high Ang-2 patient serum with endothelial cells (EC).
  
  
  RESULTS
  Ang-2 levels steadily increased from 2.6 ± 2.4 ng/mL at 0 h up to 7.3 ± 4.6 ng/mL at 24h following CPB (P<0.001). The release of Ang-2 correlated with the duration of CPB, aortic cross-clamp time, and post-CPB lactate levels. Changes in Ang-2 during follow-up correlated with partial pressure of oxygen in arterial blood (PaO(2))/fraction of inspired oxygen (FiO(2)) ratio, alveolar-arterial oxygen tension difference (AaDO(2)), hemodynamics, fluid balance, and disease severity measures. Ang-2 levels at 12h predicted the duration of MV, ICU-LOS, and hospital mortality. High Ang-2 patient sera disrupted EC architecture in vitro, an effect reversed by treatment with the competitive Tie2 ligand angiopoietin-1 (Ang-1).
  
  
  CONCLUSIONS
  Collectively, our results suggest that Ang-2 is a putative mediator of endothelial barrier dysfunction after CPB. These findings suggest that targeting the Ang/Tie2 pathway may mitigate organ dysfunction and improve outcome in patients undergoing CPB.
authors: Department of Nephrology & Hypertension, Hannover Medical School, Carl-Neuberg Strasse 1, D- 30625, Hannover, Germany.
authors: Christian
authors: C
authors: Clajus
authors: Alexander
authors: A
authors: Lukasz
authors: Sascha
authors: S
authors: David
authors: Barbara
authors: B
authors: Hertel
authors: Ralf
authors: R
authors: Lichtinghagen
authors: Samir M
authors: SM
authors: Parikh
authors: André
authors: A
authors: Simon
authors: Issam
authors: I
authors: Ismail
authors: Hermann
authors: H
authors: Haller
authors: Philipp
authors: P
authors: Kümpers
mesh_terms: D000328:Adult; D000368:Aged; D042702:Angiopoietin-2 / Q000097:blood*; D002196:Capillaries / Q000473:pathology / Q000503:physiopathology; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004727:Endothelium / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D000860:Hypoxia / Q000097:blood / Q000473:pathology / Q000503:physiopathology; D053208:Kaplan-Meier Estimate; D008297:Male; D018613:Microscopy, Confocal; D012121:Respiration, Artificial; D016896:Treatment Outcome
chemical_list: D042702:Angiopoietin-2