title: Geranylgeranylacetone protects the heart via caveolae and caveolin-3.
abstract: OBJECTIVE
  Geranylgeranylacetone (GGA) is commonly utilized to protect the gastric mucosa in peptic ulcer disease. Recently GGA has been shown to protect the myocardium from ischemia/reperfusion by activating heat shock proteins. However, the exact mechanism as to how GGA activates these protective proteins is unknown. Caveolae and caveolin-3 (Cav-3) have been implicated in ischemia, anesthetic, and opioid induced cardiac protection. Given the lipophilic nature of GGA it is our hypothesis that GGA induced cardiac protection requires caveolae and Cav-3.
  
  
  METHODS
  We used an in vivo mouse model of ischemia-reperfusion injury and performed biochemical assays in excised hearts.
  
  
  RESULTS
  GGA treated control mice revealed increased caveolae formation and caveolin-3 in buoyant fractions, mediating heat shock protein 70 activation. Furthermore, control mice treated with GGA were protected against ischemia/reperfusion injury whereas Cav-3 knockout (Cav-3 KO) mice were not. Troponin levels confirmed myocardial damage. Finally, Cav-3 KO mice treated with GGA were not protected against mitochondrial swelling whereas control mice had significant protection.
  
  
  CONCLUSIONS
  This study showed that caveolae and caveolin-3 are essential in facilitating GGA induced cardiac protection by optimizing spatial and temporal signaling to the mitochondria.
authors.affiliation: Department of Anesthesiology, University of Tokushima, Tokushima, Japan. Electronic address: tsutsumi@tokushima-u.ac.jp.
authors.forename: Yasuo M
authors.initials: YM
authors.lastname: Tsutsumi
authors.affiliation: Department of Nutrition, University of Tokushima, Tokushima, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Tsutsumi
authors.affiliation: Department of Anesthesiology, University of Tokushima, Tokushima, Japan.
authors.forename: Yousuke T
authors.initials: YT
authors.lastname: Horikawa
authors.affiliation: Department of Anesthesiology, University of Tokushima, Tokushima, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Department of Anesthesiology, University of Tokushima, Tokushima, Japan.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Hamaguchi
authors.affiliation: Cardiovascular Research Institute, Yokohama City University, Yokohama, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
authors.affiliation: Cardiovascular Research Institute, Yokohama City University, Yokohama, Japan.
authors.forename: Utako
authors.initials: U
authors.lastname: Yokoyama
authors.affiliation: Department of Anesthesiology, University of Tokushima, Tokushima, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Kasai
authors.affiliation: Department of Anesthesiology, University of Tokushima, Tokushima, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Kambe
authors.affiliation: Department of Anesthesiology, University of Tokushima, Tokushima, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D021941:Caveolae / Q000187:drug effects*; D051244:Caveolin 3 / Q000235:genetics / Q000378:metabolism*; D004224:Diterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008933:Mitochondrial Swelling / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D014336:Troponin / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D051244:Caveolin 3; D004224:Diterpenes; D014336:Troponin; C031049:geranylgeranylacetone
keywords: Cardiac protection; Caveolae; Caveolin; Geranylgeranylacetone; Heat shock protein