title: Inhibition of cell surface expression of endothelial adhesion molecules by ursolic acid prevents intimal hyperplasia of venous bypass grafts in rats.
abstract: OBJECTIVE
  Despite rapid progress in surgical techniques, there is still a significant lack of surgery-supportive pharmacological treatments. The aim of this study was to test the hypothesis that ursolic acid (UA) may prevent intimal hyperplasia of venous bypass grafts.
  
  
  METHODS
  The hypothesis was tested by means of primary cell isolation and culture followed by real-time polymerase chain reaction, western blotting, fluorescence microscopy and fluorescence-activated cell sorting analyses, as well as an in vivo rat model for intimal hyperplasia of venous bypass grafts and immunohistochemistry and histochemistry.
  
  
  RESULTS
  The local application of UA significantly inhibited intimal hyperplasia in vivo (intimal thickness control: 25 µm, UA group: 18 µM-8 weeks after surgery). The UA treatment of grafts significantly resulted in reduced endothelial vascular cell adhesion molecule-1 (VCAM-1) expression, reduced infiltration of the grafts vessel wall by CD45-positive cells and increased smooth muscle cell (SMC) death. In in vitro condition, it could be shown that UA inhibits VCAM-1 expression downstream of NFκB and is likely to interfere with VCAM-1 protein synthesis in endothelial cells. Quantification of cell death in vascular smooth muscle cells treated with UA indicated that UA is a potent inducer of SMC apoptosis.
  
  
  CONCLUSIONS
  Our results suggest that UA-mediated inhibition of endothelial VCAM-1 expression reduces the infiltration of venous bypass grafts by CD45-positive cells and inhibits intimal hyperplasia. Apoptosis induction in SMCs may be another method in which UA reduces intimal thickening. UA may constitute a surgery-supportive pharmacon that reduces intimal hyperplasia of vein grafts.
authors.affiliation: Department of Cardiac Surgery,  Medical University of Vienna, Vienna,  Austria.
authors.forename: Iris
authors.initials: I
authors.lastname: Zeller
authors.forename: Dominik
authors.initials: D
authors.lastname: Wiedemann
authors.forename: Stefan
authors.initials: S
authors.lastname: Schwaiger
authors.forename: Marlies
authors.initials: M
authors.lastname: Stelzmüller
authors.forename: Simone
authors.initials: S
authors.lastname: Kreutmayer
authors.forename: Oliver
authors.initials: O
authors.lastname: Leberfing
authors.forename: Hermann
authors.initials: H
authors.lastname: Stuppner
authors.forename: David
authors.initials: D
authors.lastname: Bernhard
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002317:Cardiovascular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D006083:Graft Occlusion, Vascular / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D007601:Jugular Veins / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D016896:Treatment Outcome; D014315:Triterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D058017:Vascular Grafting; D000097245:Ursolic Acid
chemical_list: D015415:Biomarkers; D002317:Cardiovascular Agents; D017493:Leukocyte Common Antigens; D014315:Triterpenes; D019010:Vascular Cell Adhesion Molecule-1; D000097245:Ursolic Acid; C516771:Ptprc protein, rat