title: Visceral adipose tissue-derived serine proteinase inhibitor inhibits apoptosis of endothelial cells as a ligand for the cell-surface GRP78/voltage-dependent anion channel complex.
abstract: BACKGROUND
  Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified from visceral adipose tissues of genetically obese rats.
  
  
  OBJECTIVE
  The role of vaspin in the diabetic vascular complications remains elusive, and we investigated the effects of vaspin on the vascular function under the diabetic milieu.
  
  
  RESULTS
  Adenovirus carrying the full length of the vaspin gene (Vaspin-Ad) ameliorated intimal proliferation of balloon-injured carotid arteries in diabetic Wistar rats. The expression of Ccl2, Pdgfb, and Pdgfrb genes was significantly reduced by the treatment of Vaspin-Ad. In cuff-injured femoral arteries, the intimal proliferation was ameliorated in vaspin transgenic (Vaspin Tg) mice. The application of recombinant vaspin and Vaspin-Ad promoted the proliferation and inhibited the apoptosis of human aortic endothelial cells. Adenovirus expressing vaspin with calmodulin and streptavidin-binding peptides was applied to human aortic endothelial cells, subjected to tandem tag purification and liquid chromatography-tandem mass spectrometry, and we identified GRP78 (78-kDa glucose-regulated protein) as an interacting molecule. The complex formation of vaspin, GRP78, and voltage-dependent anion channel on the plasma membrane was confirmed by the immunoprecipitation studies using aortas of Vaspin Tg mice. The binding assay using (125)I-vaspin in human aortic endothelial cells revealed high-affinity binding (dissociation constant = 0.565×10(-9) m) by the treatment of 5 μM thapsigargin, which recruited GRP78 from the endoplasmic reticulum to plasma membrane by inducing endoplasmic reticulum stress. In human aortic endothelial cells, vaspin induced phosphorylation of Akt and inhibited the kringle 5-induced Ca(2+) influx and subsequent apoptosis.
  
  
  CONCLUSIONS
  Vaspin is a novel ligand for the cell-surface GRP78/voltage-dependent anion channel complex in endothelial cells and promotes proliferation, inhibits apoptosis, and protects vascular injuries in diabetes mellitus.
authors: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan.
authors: Atsuko
authors: A
authors: Nakatsuka
authors: Jun
authors: J
authors: Wada
authors: Izumi
authors: I
authors: Iseda
authors: Sanae
authors: S
authors: Teshigawara
authors: Kanji
authors: K
authors: Higashio
authors: Kazutoshi
authors: K
authors: Murakami
authors: Motoko
authors: M
authors: Kanzaki
authors: Kentaro
authors: K
authors: Inoue
authors: Takahiro
authors: T
authors: Terami
authors: Akihiro
authors: A
authors: Katayama
authors: Kazuyuki
authors: K
authors: Hida
authors: Jun
authors: J
authors: Eguchi
authors: Daisuke
authors: D
authors: Ogawa
authors: Yasushi
authors: Y
authors: Matsuki
authors: Ryuji
authors: R
authors: Hiramatsu
authors: Hideo
authors: H
authors: Yagita
authors: Shigeru
authors: S
authors: Kakuta
authors: Yoichiro
authors: Y
authors: Iwakura
authors: Hirofumi
authors: H
authors: Makino
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D054392:Adipokines / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D004730:Endothelium, Vascular / Q000473:pathology*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051381:Rats; D017208:Rats, Wistar; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D013311:Streptozocin / Q000009:adverse effects; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism*
chemical_list: D054392:Adipokines; D000091342:Endoplasmic Reticulum Chaperone BiP; C051684:GRP78 protein, rat; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D008024:Ligands; C507339:SERPINA12 protein, human; C506516:Serpina12 protein, rat; D015843:Serpins; D050994:Voltage-Dependent Anion Channels; C577327:vaspin protein, mouse; D013311:Streptozocin