title: Ursolic acid causes DNA-damage, p53-mediated, mitochondria- and caspase-dependent human endothelial cell apoptosis, and accelerates atherosclerotic plaque formation in vivo.
abstract: OBJECTIVE
  The plant derived triterpene ursolic acid (UA) has been intensively studied in the past; mainly as an anti-cancer compound and for its cardiovascular protective properties. Based on the controversy of reports suggesting anti-angiogenic and cytotoxic effects of UA on one side and cardiovascular and endothelial protective effects on the other side, we decided to assess UA effects on primary human endothelial cells in vitro and atherosclerotic plaque formation in vivo.
  
  
  RESULTS
  Our in vitro analyses clearly show that UA inhibits endothelial proliferation and is a potent inducer of endothelial cell death. UA causes DNA-damage, followed by the activation of a p53-, BAK-, and caspase-dependent cell-death pathway. Oral application of UA in APO E knockout mice potently stimulated atherosclerotic plaque formation in vivo, which was correlated with decreased serum levels of the athero-protective cytokine IL-5.
  
  
  CONCLUSIONS
  Due the potent endothelial cell death inducing activity of UA, a systemic application of UA in the treatment of cardiovascular diseases seems unfavourable. UA as an anti-angiogenesis, anti-cancer and - locally applied - cardiovascular drug may be helpful. The DNA damaging activity of UA may however constitute a serious problem.
authors.affiliation: Cardiac Surgery, Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Messner
authors.forename: Iris
authors.initials: I
authors.lastname: Zeller
authors.forename: Christian
authors.initials: C
authors.lastname: Ploner
authors.forename: Sandra
authors.initials: S
authors.lastname: Frotschnig
authors.forename: Thomas
authors.initials: T
authors.lastname: Ringer
authors.forename: Anneliese
authors.initials: A
authors.lastname: Steinacher-Nigisch
authors.forename: Andreas
authors.initials: A
authors.lastname: Ritsch
authors.forename: Günther
authors.initials: G
authors.lastname: Laufer
authors.forename: Christian
authors.initials: C
authors.lastname: Huck
authors.forename: David
authors.initials: D
authors.lastname: Bernhard
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications / Q000235:genetics / Q000378:metabolism; D015848:Interleukin-5 / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D058226:Plaque, Atherosclerotic / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D014315:Triterpenes / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism; D000097245:Ursolic Acid
chemical_list: D001057:Apolipoproteins E; D020169:Caspases; D015848:Interleukin-5; D014315:Triterpenes; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; D000097245:Ursolic Acid; C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; C495901:TP53 protein, human