title: Geranylgeranylacetone and volatile anesthetic-induced cardiac protection synergism is dependent on caveolae and caveolin-3.
abstract: OBJECTIVE
  Pharmacological preconditioning, including that with geranylgeranylacetone (GGA) and volatile anesthetics, has been shown to confer cardiac protection from ischemia/reperfusion injury although the mechanisms for this protection are poorly understood. Caveolins, integral membrane proteins that act as scaffolding proteins in caveolar membranes, localize molecules involved in cardiac protection. We have tested the hypothesis that caveolin-3 (Cav-3), the predominant isoform in cardiac myocytes, is essential for the synergistic effect observed between GGA and volatile anesthetics.
  
  
  METHODS
  Mice were randomly assigned to receive GGA, isoflurane [0.5 and 1.0 minimum alveolar concentration (MAC)], or GGA + isoflurane (0.5 MAC). An in vivo mouse model of ischemia/reperfusion injury was tested in wild-type and Cav-3 knockout mice, and the infarct size was determined. Biochemical assays were also performed in excised hearts.
  
  
  RESULTS
  Geranylgeranylacetone and therapeutic isoflurane (1.0 MAC) independently reduced infarct size (31.6 ± 6.1 and 28.0 ± 5.0% of the area at risk, respectively; n = 10) as compared to the controls (45.8 ± 9.4%; n = 10). The combination GGA + sub-therapeutic isoflurane (0.5 MAC) further decreased the infarct size to 19.3 ± 5.1% (n = 10). Preconditioning [GGA, isoflurane (1.0 MAC), and GGA + isoflurane] increased the amount of Cav-3 protein in the discontinuous sucrose-gradient buoyant fractions. Additionally, cardiac protection was not observed in Cav-3 knockout mice following the administration of GGA, isoflurane, and GGA + isoflurane.
  
  
  CONCLUSIONS
  Combined administration of GGA + isoflurane had a synergistic effect, enhancing the protection against myocardial infarction to a greater extent than either drug alone. This beneficial effect is mediated by Cav-3 expression.
authors.affiliation: Department of Anesthesiology, University of Tokushima, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan, tsutsumi@tokushima-u.ac.jp.
authors.forename: Yasuo M
authors.initials: YM
authors.lastname: Tsutsumi
authors.forename: Rie
authors.initials: R
authors.lastname: Tsutsumi
authors.forename: Yousuke T
authors.initials: YT
authors.lastname: Horikawa
authors.forename: Yoko
authors.initials: Y
authors.lastname: Sakai
authors.forename: Eisuke
authors.initials: E
authors.lastname: Hamaguchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitahata
authors.forename: Asuka
authors.initials: A
authors.lastname: Kasai
authors.forename: Noriko
authors.initials: N
authors.lastname: Kambe
authors.forename: Katsuya
authors.initials: K
authors.lastname: Tanaka
mesh_terms: D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D021941:Caveolae / Q000378:metabolism; D051244:Caveolin 3 / Q000235:genetics / Q000378:metabolism; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D007530:Isoflurane / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism
chemical_list: D018685:Anesthetics, Inhalation; D051244:Caveolin 3; D004224:Diterpenes; D007530:Isoflurane; C031049:geranylgeranylacetone