title: Waon therapy upregulates Hsp90 and leads to angiogenesis through the Akt-endothelial nitric oxide synthase pathway in mouse hindlimb ischemia.
abstract: BACKGROUND
  Thermal therapy, namely Waon therapy, has previously been reported to regulate nitric oxide (NO) and endothelial NO synthase (eNOS) and augment ischemia-induced angiogenesis in mice and improve limb ischemia in patients with peripheral artery disease. The aim of this study was to clarify the precise mechanism by which Waon therapy augments angiogenesis in mice with hindlimb ischemia.
  
  
  RESULTS
  Unilateral hindlimb ischemia was induced in apolipoprotein E-deficient mice and Waon therapy was performed for 5 weeks. Heat shock protein 90 (Hsp90), phosphorylated-Akt, and phosphorylated-eNOS were detected in arterial endothelial cells of ischemic hindlimbs and all were upregulated by Waon therapy compared to controls. Waon therapy also increased serum concentrations of nitrite and nitrate. Capillary density and the ischemic limb/normal side blood perfusion ratio monitored by laser Doppler perfusion imaging in the Waon therapy group were significantly increased beyond those in the control group. The effect of Waon therapy on angiogenesis through the activation of the Hsp90/Akt/eNOS pathway was attenuated by the administration of a Hsp90 inhibitor.
  
  
  CONCLUSIONS
  It is suggested that Waon therapy upregulates Hsp90, which contributes to the activation of the Akt/eNOS/NO pathway, and induces angiogenesis in mice with hindlimb ischemia.
authors.affiliation: Department of Cardiovascular, Respiratory and Metabolic Medicine, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Miyauchi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Miyata
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Akasaki
authors.forename: Narisato
authors.initials: N
authors.lastname: Hamada
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shirasawa
authors.forename: Yuko
authors.initials: Y
authors.lastname: Furusho
authors.forename: Chuwa
authors.initials: C
authors.lastname: Tei
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001158:Arteries / Q000201:enzymology / Q000503:physiopathology; D016227:Benzoquinones / Q000494:pharmacology; D001783:Blood Flow Velocity; D002196:Capillaries / Q000201:enzymology / Q000503:physiopathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006614:Hindlimb; D006979:Hyperthermia, Induced; D007150:Immunohistochemistry; D007511:Ischemia / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D017078:Laser-Doppler Flowmetry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012039:Regional Blood Flow; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D042501:Angiogenic Proteins; D001057:Apolipoproteins E; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt