title: Cardioprotective trafficking of caveolin to mitochondria is Gi-protein dependent.
abstract: BACKGROUND
  Caveolae are a nexus for protective signaling. Trafficking of caveolin to mitochondria is essential for adaptation to cellular stress though the trafficking mechanisms remain unknown. The authors hypothesized that G protein-coupled receptor/inhibitory G protein (Gi) activation leads to caveolin trafficking to mitochondria.
  
  
  METHODS
  Mice were exposed to isoflurane or oxygen vehicle (30 min, ± 36 h pertussis toxin pretreatment, an irreversible Gi inhibitor). Caveolin trafficking, cardioprotective "survival kinase" signaling, mitochondrial function, and ultrastructure were assessed.
  
  
  RESULTS
  Isoflurane increased cardiac caveolae (n = 8 per group; data presented as mean ± SD for Ctrl versus isoflurane; [caveolin-1: 1.78 ± 0.12 vs. 3.53 ± 0.77; P < 0.05]; [caveolin-3: 1.68 ± 0.29 vs. 2.67 ± 0.46; P < 0.05]) and mitochondrial caveolin levels (n = 16 per group; [caveolin-1: 0.87 ± 0.18 vs. 1.89 ± .19; P < 0.05]; [caveolin-3: 1.10 ± 0.29 vs. 2.26 ± 0.28; P < 0.05]), and caveolin-enriched mitochondria exhibited improved respiratory function (n = 4 per group; [state 3/complex I: 10.67 ± 1.54 vs. 37.6 ± 7.34; P < 0.05]; [state 3/complex II: 37.19 ± 4.61 vs. 71.48 ± 15.28; P < 0.05]). Isoflurane increased phosphorylation of survival kinases (n = 8 per group; [protein kinase B: 0.63 ± 0.20 vs. 1.47 ± 0.18; P < 0.05]; [glycogen synthase kinase 3β: 1.23 ± 0.20 vs. 2.35 ± 0.20; P < 0.05]). The beneficial effects were blocked by pertussis toxin.
  
  
  CONCLUSIONS
  Gi proteins are involved in trafficking caveolin to mitochondria to enhance stress resistance. Agents that target Gi activation and caveolin trafficking may be viable cardioprotective agents.
authors.affiliation: From the Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China (J.W., Y.Y.); VA San Diego Healthcare System, San Diego, California (P.M.P., B.P.H., D.M.R., H.H.P.); Department of Anesthesiology, University of California, San Diego, California (J.M.S., I.R.N., J.C.F., E.K., P.M.P., B.P.H., D.M.R., H.H.P.); and Heart Foundation Research Center, Griffith University, Gold Coast, Queensland, Australia (J.P.H.).
authors.forename: Jiawan
authors.initials: J
authors.lastname: Wang
authors.forename: Jan M
authors.initials: JM
authors.lastname: Schilling
authors.forename: Ingrid R
authors.initials: IR
authors.lastname: Niesman
authors.forename: John P
authors.initials: JP
authors.lastname: Headrick
authors.forename: J Cameron
authors.initials: JC
authors.lastname: Finley
authors.forename: Evan
authors.initials: E
authors.lastname: Kwan
authors.forename: Piyush M
authors.initials: PM
authors.lastname: Patel
authors.forename: Brian P
authors.initials: BP
authors.lastname: Head
authors.forename: David M
authors.initials: DM
authors.lastname: Roth
authors.forename: Yun
authors.initials: Y
authors.lastname: Yue
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
mesh_terms: D000818:Animals; D021941:Caveolae / Q000187:drug effects / Q000502:physiology; D022461:Caveolins / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007530:Isoflurane / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D037342:Pertussis Toxin / Q000494:pharmacology; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D022461:Caveolins; D007530:Isoflurane; D037342:Pertussis Toxin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D019206:GTP-Binding Protein alpha Subunits, Gi-Go