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

被引:86
作者
Nakatsuka, Atsuko [1 ]
Wada, Jun [1 ]
Iseda, Izumi [1 ]
Teshigawara, Sanae [1 ]
Higashio, Kanji [3 ]
Murakami, Kazutoshi [1 ]
Kanzaki, Motoko [1 ]
Inoue, Kentaro [1 ]
Terami, Takahiro [1 ]
Katayama, Akihiro [1 ]
Hida, Kazuyuki [1 ]
Eguchi, Jun [1 ]
Ogawa, Daisuke [2 ]
Matsuki, Yasushi [4 ]
Hiramatsu, Ryuji [4 ]
Yagita, Hideo [5 ]
Kakuta, Shigeru [6 ]
Iwakura, Yoichiro [6 ,7 ]
Makino, Hirofumi [1 ]
机构
[1] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin Sci, Okayama 7008558, Japan
[2] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Diabet Nephropathy, Okayama 7008558, Japan
[3] Metabolome Pharmaceut Inc, Tokyo, Japan
[4] Dainippon Sumitomo Pharma, Genom Sci Labs, Osaka, Japan
[5] Juntendo Univ, Sch Med, Dept Immunol, Tokyo 113, Japan
[6] Univ Tokyo, Inst Med Sci, Ctr Expt Med & Syst Biol, Tokyo, Japan
[7] Japan Sci & Technol, CREST, Saitama, Japan
基金
日本学术振兴会;
关键词
apoptosis; atherosclerosis; diabetes mellitus; endothelium; SERUM VASPIN CONCENTRATIONS; PROSTATE-CANCER CELLS; PLASMINOGEN KRINGLE-5; ADIPOKINE VASPIN; GRP78; RECEPTOR; ACTIVATION; ALPHA(2)-MACROGLOBULIN; ADIPOCYTOKINE; MIGRATION;
D O I
10.1161/CIRCRESAHA.111.300049
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Rationale: 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. Methods and 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 125I-vaspin in human aortic endothelial cells revealed high-affinity binding (dissociation constant = 0.565x10(-9) m) by the treatment of 5 mu M 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 Ca2+ 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. (Circ Res. 2013;112:771-780.)
引用
收藏
页码:771 / +
页数:17
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