title: Geranylgeranylacetone, heat shock protein 90/AMP-activated protein kinase/endothelial nitric oxide synthase/nitric oxide pathway, and endothelial function in humans.
abstract: OBJECTIVE
  Geranylgeranylacetone (GGA) induces expression of heat shock protein 90 (Hsp90), an adaptor molecule for assembly of endothelial nitric oxide synthase (eNOS) phosphorylation complex. The purpose of this study was to determine whether GGA enhances Hsp90 expression and augments endothelium-dependent vasodilation via upregulation of eNOS in humans.
  
  
  RESULTS
  We evaluated the effects of GGA on human umbilical vein endothelial cells (HUVECs) and on forearm blood flow (FBF) responses to acetylcholine and sodium nitroprusside in 40 healthy young men. Hsp90, eNOS, AMP-activated protein kinase (AMPK), and Akt expression in HUVECs and peripheral blood mononuclear cells was detected by Western blot analysis. GGA increased Hsp90 expression and phosphorylation of eNOS and AMPK but not Akt in HUVECs and increased Hsp90 expression in peripheral blood mononuclear cells. Oral administration of GGA (600 mg) augmented the FBF response to acetylcholine. Infusion of N(G)-monomethyl-l-arginine, an NO synthase inhibitor, completely abolished GGA-induced augmentation of the FBF response to acetylcholine. GGA also augmented the acetylcholine-stimulated NO release in smokers.
  
  
  CONCLUSIONS
  These findings suggest that GGA-induced activation of Hsp90/AMPK significantly increased NO-mediated vasodilation in healthy subjects, as well as in smokers. The use of GGA may be a new therapeutic approach for improving endothelial dysfunction.
authors: Department of Cardiovascular Medicine, Hiroshima University.
authors: Noritaka
authors: N
authors: Fujimura
authors: Daisuke
authors: D
authors: Jitsuiki
authors: Tatsuya
authors: T
authors: Maruhashi
authors: Shinsuke
authors: S
authors: Mikami
authors: Yumiko
authors: Y
authors: Iwamoto
authors: Masato
authors: M
authors: Kajikawa
authors: Kazuaki
authors: K
authors: Chayama
authors: Yasuki
authors: Y
authors: Kihara
authors: Kensuke
authors: K
authors: Noma
authors: Chikara
authors: C
authors: Goto
authors: Yukihito
authors: Y
authors: Higashi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000109:Acetylcholine / Q000494:pharmacology; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D004224:Diterpenes / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology*; D005542:Forearm / Q000098:blood supply; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D055815:Young Adult
chemical_list: D004224:Diterpenes; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; D000109:Acetylcholine; C031049:geranylgeranylacetone