title: Aprotinin preserves cellular junctions and reduces myocardial edema after regional ischemia and cardioplegic arrest.
abstract: BACKGROUND
  Cardiac surgery with cardiopulmonary bypass (CPB) and cardioplegic arrest has been associated with myocardial edema attributable to vascular permeability, which is regulated in part by thrombin-induced alterations in cellular junctions. Aprotinin has been demonstrated to prevent activation of the thrombin protease-activated receptor, and we hypothesized that aprotinin preserves myocardial cellular junctions and prevents myocardial edema in a porcine model of regional ischemia and cardioplegic arrest.
  
  
  RESULTS
  Fourteen pigs were subjected to 30 minutes of regional ischemia, followed by 60 minutes of CPB, with 45 minutes of crystalloid cardioplegia, then 90 minutes of post-CPB reperfusion. The treatment group (n=7) was administered aprotinin (40,000 kallikrein inhibitor units [KIU]/kg loading dose, 40,000 KIU/kg pump prime, and 10,000 KIU/kg per hour continuous infusion). Control animals (n=7) received normal saline. Myocardial vascular endothelial (VE)-cadherin, beta-catenin and gamma-catenin, and associated mitogen-activated protein kinase (MAPK) pathways were assessed by immunoblot and immunoprecipitation. Histologic analysis of the cellular junctions was done by immunofluorescence. Myocardial tissue water content was measured. VE-cadherin, beta-catenin, and gamma-catenin levels were significantly greater in the aprotinin group (all P<0.05). Immunfluorescence confirmed that aprotinin prevented loss of coronary endothelial adherens junction continuity. Aprotinin reduced tyrosine phosphorylation in myocardial tissue sections. Phospho-p38 activity was approximately 30% lower in the aprotinin group (P=0.007). The aprotinin group demonstrated decreased myocardial tissue water content (81.2+/-0.5% versus 83.5+/-0.3%; P=0.01) and reduced intravenous fluid requirements (2.9+/-0.2 L versus 4.0+/-0.4 L; P=0.03).
  
  
  CONCLUSIONS
  Aprotinin preserves adherens junctions after regional ischemia and cardioplegic arrest through a mechanism potentially involving the p38 MAPK pathway, resulting in preservation of the VE barrier and reduced myocardial tissue edema.
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Tanveer A
authors.initials: TA
authors.lastname: Khan
authors.forename: Cesario
authors.initials: C
authors.lastname: Bianchi
authors.forename: Eugenio
authors.initials: E
authors.lastname: Araujo
authors.forename: Pierre
authors.initials: P
authors.lastname: Voisine
authors.forename: Shu-Hua
authors.initials: SH
authors.lastname: Xu
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D022005:Adherens Junctions / Q000187:drug effects*; D000818:Animals; D015703:Antigens, CD; D007611:Aprotinin / Q000627:therapeutic use*; D001834:Body Water; D015820:Cadherins / Q000032:analysis; D002199:Capillary Permeability / Q000187:drug effects; D009202:Cardiomyopathies / Q000209:etiology / Q000517:prevention & control*; D004341:Drug Evaluation; D004487:Edema / Q000209:etiology / Q000517:prevention & control*; D006324:Heart Arrest, Induced / Q000009:adverse effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D017202:Myocardial Ischemia / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D017680:Potassium Compounds / Q000494:pharmacology / Q000633:toxicity; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D034421:Sus scrofa; D051176:beta Catenin / Q000032:analysis; D051185:gamma Catenin / Q000032:analysis; D048051:p38 Mitogen-Activated Protein Kinases / Q000032:analysis; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D007611:Aprotinin; D015820:Cadherins; D017680:Potassium Compounds; D051176:beta Catenin; D051185:gamma Catenin; D048051:p38 Mitogen-Activated Protein Kinases; D000099152:Cadherin 5; C018369:potassium cardioplegic solution