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Hideyuki Yamawaki - One of the best experts on this subject based on the ideXlab platform.
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Vaspin prevents elevation of blood pressure through inhibition of peripheral vascular remodelling in spontaneously hypertensive rats
Acta Physiologica, 2016Co-Authors: Satoshi Kameshima, Yuzaburo Sakamoto, Muneyoshi Okada, Hideyuki YamawakiAbstract:Aim Visceral adipose tissue-derived serine protease inhibitor (Vaspin) is a relatively novel adipocytokine with protective effects on metabolic diseases including obesity and type II diabetes. We have previously demonstrated that Vaspin exerts anti-inflammatory and antimigratory roles through antioxidative effects in vascular smooth muscle cells. As inflammatory responses and migration of smooth muscle in peripheral vascular wall are key mechanisms for the pathogenesis of hypertension, we hypothesized that Vaspin could prevent the development of hypertension in in vivo hypertensive animal model. Methods Vaspin (1 μg kg−1 day−1) was administered intraperitoneally to 5-week-old male spontaneously hypertensive rats (SHR) for 4 weeks. Superior mesenteric artery was isolated and used for measurement of isometric contraction and histological analysis. Results Long-term Vaspin treatment significantly prevented an elevation of systolic blood pressure (SBP) at 8 weeks of age. Vaspin had no effect on reactivity of isolated mesenteric artery from SHR. In contrast, Vaspin significantly inhibited mesenteric arterial wall hypertrophy in SHR. Moreover, Vaspin significantly inhibited an increase of tumour necrosis factor-α expression and a production of reactive oxygen species in isolated mesenteric artery from SHR. Conclusion This study for the first time demonstrates that Vaspin prevents the increase of SBP in SHR through inhibiting peripheral vascular hypertrophy possibly via antioxidative and anti-inflammatory mechanisms.
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Vaspin prevents methylglyoxal induced apoptosis in human vascular endothelial cells by inhibiting reactive oxygen species generation
Acta Physiologica, 2013Co-Authors: Sukanya Phalitakul, Muneyoshi Okada, Yukio Hara, Hideyuki YamawakiAbstract:AbstractAim: Vaspin (visceral adipose tissue-derived serine protease inhibitor) is anovel adipocytokine found in visceral white adipose tissues of obese type 2diabetic rats. We have previously shown that Vaspin has anti-inflammatoryand antimigratory effects in vascular smooth muscle cells. Methylglyoxal(MGO) is an active metabolite of glucose and mediates diabetic vascularcomplications including endothelial cell (EC) apoptosis. Nonetheless,effects of Vaspin on MGO-induced apoptosis of vascular EC remain to bedetermined. We investigated the effects of Vaspin on MGO-induced apop-tosis of human umbilical vein ECs (HUVECs).Methods: Human umbilical vein ECs were treated with MGO (560 l M ,12 h) in the absence or presence of Vaspin (1 ng mL 1 , pre-treatment for2 h). Cell death was evaluated by a cell counting assay. Apoptosis wasdetermined by a terminal deoxyribonucleotide transferase-mediated deoxy-uridine triphosphate nick-end labelling (TUNEL) assay. Cleaved caspase-3expression was determined by Western blotting. Reactive oxygen species(ROS) generation was fluorometrically measured using 2′,7′-dichlorodihy-drofluorescein diacetate. NADPH oxidase (NOX) activity was determinedby a lucigenin assay.Results: Vaspin significantly inhibited MGO-induced HUVEC death.Vaspin significantly attenuated MGO-increased TUNEL-positive ECs.Moreover, Vaspin significantly inhibited MGO-induced caspase-3 cleavage.Vaspin significantly inhibited MGO-induced ROS generation as well asNOX activation.Conclusions: The present results for the first time demonstrate that Vaspininhibits MGO-induced EC apoptosis by preventing caspase-3 activationvia the inhibition of NOX-derived ROS generation.Keywords adipocytokine, apoptosis, methylglyoxal, reactive oxygenspecies, vascular endothelial cell.
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a novel adipocytokine Vaspin inhibits platelet derived growth factor bb induced migration of vascular smooth muscle cells
Biochemical and Biophysical Research Communications, 2012Co-Authors: Sukanya Phalitakul, Muneyoshi Okada, Yukio Hara, Hideyuki YamawakiAbstract:Vaspin is a novel adipocytokine originally identified in visceral white adipose tissues of Otsuka Long-Evans Tokushima fatty rats, an animal model of type 2 diabetes. We have previously shown that Vaspin has anti-inflammatory effects in vascular smooth muscle cells (SMCs). SMCs migration is an important process for development atherosclerosis. However, effects of Vaspin on SMCs migration remain to be clarified. Rat mesenteric arterial SMCs were treated with platelet-derived growth factor (PDGF)-BB (10 ng/ml, 90 min) in the absence or presence of Vaspin (0.01-10 ng/ml, pretreatment for 2h). SMCs migration was evaluated by a Boyden chamber assay. Western blotting was performed to analyze cellular signals. Reactive oxygen species (ROS) generation was fluorometrically measured using 2',7'-dichlorofluorescein diacetate. Vaspin significantly inhibited PDGF-BB-induced SMCs migration. Vaspin significantly inhibited PDGF-BB-induced phosphorylation of p38 and heat shock protein (HSP) 27 as well as ROS generation. SMCs migration was blocked by an inhibitor of p38 or an anti-oxidant drug, N-acetyl-l-cysteine (NAC). NAC significantly inhibited the PDGF-BB-induced phosphorylation of p38 and HSP27. In addition, Vaspin inhibited PDGF-BB-induced actin cytoskeletal reorganization (lamellipodia formation) as revealed by a rhodamine phalloidin staining. The present study for the first time revealed that Vaspin inhibits PDGF-BB-induced SMCs migration through inhibiting p38/HSP27 signals via preventing the ROS generation.
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Vaspin prevents tnf α induced intracellular adhesion molecule 1 via inhibiting reactive oxygen species dependent nf κb and pkcθ activation in cultured rat vascular smooth muscle cells
Pharmacological Research, 2011Co-Authors: Sukanya Phalitakul, Muneyoshi Okada, Yukio Hara, Hideyuki YamawakiAbstract:Abstract Vaspin (visceral adipose tissue-derived serine protease inhibitor) was recently identified as a novel adipocytokine with insulin-sensitizing effects. We hypothesized that Vaspin could play a role in vascular inflammation. To test the hypothesis, we investigated the effects of Vaspin on TNF-α-stimulated vascular smooth muscle cells (SMCs) focusing on inflammatory signal transduction. Vascular SMCs from mesenteric artery of male Wistar rats were treated with TNF-α (5–10 ng/ml, 20 min–6 h) in the absence or presence of Vaspin (1–300 ng/ml, pretreatment for 24 h). Western blotting was performed to analyze the cellular signal. Reactive oxygen species (ROS) generation was fluorometrically measured using 2′,7′-diclorofluorescein diacetate. Vaspin alone treatment had no effect on vascular SMCs morphology and cellular signal. Vaspin significantly decreased the TNF-α-induced monocyte adhesion to SMCs. Vaspin significantly inhibited the protein expression of intracellular adhesion molecule (ICAM)-1 and the phosphorylation of NF-κB and protein kinase C (PKC)θ induced by TNF-α. Both of NF-κB and novel PKC inhibitors significantly attenuated the TNF-α-induced ICAM-1 expression. Moreover, Vaspin inhibited TNF-α-induced ROS generation. An anti-oxidant, N-acetyl- l -cysteine blocked the TNF-α-induced activation of NF-κB, PKCθ and expression of ICAM-1. The present results demonstrated for the first time that Vaspin inhibits TNF-α-induced expression of ICAM-1 via preventing the ROS generation and subsequent activation of NF-κB and PKCθ. Consequently, Vaspin could play inhibitory roles on inflammatory states of vascular SMCs.
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Vaspin can not inhibit tnf α induced inflammation of human umbilical vein endothelial cells
Journal of Veterinary Medical Science, 2009Co-Authors: Muneyoshi Okada, Hideyuki Yamawaki, F U Bendong, Yukio HaraAbstract:Visceral adipose tissue-derived serine protease inhibitor (Vaspin) has been recently identified as an adipocytokine in a rat model of type 2 diabetes. Adipocytokines may directly influence the function of endothelial cells (ECs) and modulate inflammatory states. We therefore assessed the effects of Vaspin on basal and TNF-alpha-stimulated human umbilical vein ECs. Vaspin (10-100 ng/ml, 24 hr) had no effects on both basal ECs morphology and TNF-alpha-induced (10 ng/ml, 24 hr) morphological damages. Vaspin did not inhibit the TNF-alpha (20 min) activation of JNK, p38 and NF-kappaB, but only slightly inhibited Akt. Furthermore, Vaspin did not decrease the TNF-alpha (24 hr) induction of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, endothelial selectin, and cyclooxygenase-2 protein expression as well as monocyte chemotactic protein-1, tissue factor, and plasmogen activator inhibitor-1 mRNA expression. The present results indicate that Vaspin has no effects on normal ECs, and can not prevent TNF-alpha-induced inflammatory injury.
Matthias Bluher - One of the best experts on this subject based on the ideXlab platform.
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circulating adipokine Vaspin is associated with serum lipid profiles in humans
Lipids, 2019Co-Authors: Jana Breitfeld, Peter Kovacs, Michael Stumvoll, Matthias Bluher, Norman Wiele, Beate Gutsmann, Markus Scholz, Anke TonjesAbstract:Vaspin, visceral adipose tissue-derived serpin, is an adipokine ameliorating insulin resistance in obesity. Here, we investigated the role of Vaspin and its genetic variants in lipid metabolism. We measured serum Vaspin concentrations by ELISA in 823 metabolically well-characterized Caucasian subjects (Sorbs from Germany). Furthermore, we genotyped 30 representative single nucleotide polymorphisms (SNP) in two independent cohorts with metabolic phenotyping, the Sorbs (N = 823) and Leipzig (N = 919), and conducted genotype-phenotype association analyses. Circulating Vaspin strongly correlated with triacylglycerol levels (TAG; p = 1.079 × 10-11 ), and moderately with apolipoprotein A1 and low-density lipoprotein cholesterol (p = 0.026). Genetic variants in Vaspin were nominally associated with cholesterol, high-density and low-density lipoprotein (HDL-chol, LDL-chol), lipoprotein A, and apolipoprotein B as well as with TAG and free fatty acids (all p < 0.05 adjusted for age, sex, and body mass index [BMI]). Mendelian randomization analysis using Vaspin SNP as an instrumental variable showed borderline influence of Vaspin on LDL-chol levels (p = 0.05). Associations of Vaspin and its genetic variation with metabolic traits suggest a role of Vaspin in human lipid metabolism.
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Brown adipose tissue (BAT) specific Vaspin expression is increased after obesogenic diets and cold exposure and linked to acute changes in DNA-methylation.
Molecular metabolism, 2017Co-Authors: Juliane Weiner, Nora Kloting, Peter Kovacs, Michael Stumvoll, Matthias Bluher, Kerstin Rohde, Kerstin Krause, Konstanze Zieger, Susan Kralisch, Yvonne BöttcherAbstract:Abstract Objective Several studies have demonstrated anti-diabetic and anti-obesogenic properties of visceral adipose tissue-derived serine protease inhibitor (Vaspin) and so evoked its potential use for treatment of obesity-related diseases. The aim of the study was to unravel physiological regulators of Vaspin expression and secretion with a particular focus on its role in brown adipose tissue (BAT) biology. Methods We analyzed the effects of obesogenic diets and cold exposure on Vaspin expression in liver and white and brown adipose tissue (AT) and plasma levels. Vaspin expression was analyzed in isolated white and brown adipocytes during adipogenesis and in response to adrenergic stimuli. DNA-methylation within the Vaspin promoter was analyzed to investigate acute epigenetic changes after cold-exposure in BAT. Results Our results demonstrate a strong induction of Vaspin mRNA and protein expression specifically in BAT of both cold-exposed and high-fat (HF) or high-sugar (HS) fed mice. While obesogenic diets also upregulated hepatic Vaspin mRNA levels, cold exposure tended to increase Vaspin gene expression of inguinal white adipose tissue (iWAT) depots. Concomitantly, Vaspin plasma levels were decreased upon obesogenic or thermogenic triggers. Vaspin expression was increased during adipogenesis but unaffected by sympathetic activation in brown adipocytes. Analysis of Vaspin promoter methylation in AT revealed lowest methylation levels in BAT, which were acutely reduced after cold exposure. Conclusions Our data demonstrate a novel BAT-specific regulation of Vaspin gene expression upon physiological stimuli in vivo with acute epigenetic changes that may contribute to cold-induced expression in BAT. We conclude that these findings indicate functional relevance and potentially beneficial effects of Vaspin in BAT function.
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Vaspin inhibits kallikrein 7 by serpin mechanism
Cellular and Molecular Life Sciences, 2013Co-Authors: John T Heiker, Nora Kloting, Peter Kovacs, Bartholomeus E Kuettner, Norbert Strater, S Schultz, Matthias Kern, Michael Stumvoll, Matthias Bluher, Annette G BecksickingerAbstract:The molecular target of the adipokine Vaspin (visceral adipose tissue-derived serpin; serpinA12) and its mode of action are unknown. Here, we provide the Vaspin crystal structure and identify human kallikrein 7 (hK7) as a first protease target of Vaspin inhibited by classical serpin mechanism with high specificity in vitro. We detect Vaspin–hK7 complexes in human plasma and find co-expression of both proteins in murine pancreatic β-cells. We further demonstrate that hK7 cleaves human insulin in the A- and B-chain. Vaspin treatment of isolated pancreatic islets leads to increased insulin concentration in the media upon glucose stimulation without influencing insulin secretion. By application of Vaspin and generated inactive mutants, we find the significantly improved glucose tolerance in C57BL/6NTac and db/db mice treated with recombinant Vaspin fully dependent on the Vaspin serpin activity and not related to Vaspin-mediated changes in insulin sensitivity as determined by euglycemic-hyperinsulinemic clamp studies. Improved glucose metabolism could be mediated by increased insulin plasma concentrations 150 min after a glucose challenge in db/db mice, supporting the hypothesis that Vaspin may inhibit insulin degradation by hK7 in the circulation. In conclusion, we demonstrate the inhibitory serpin nature and the first protease target of the adipose tissue-derived serpin Vaspin, and our findings suggest hK7 inhibition by Vaspin as an underlying physiological mechanism for its compensatory actions on obesity-induced insulin resistance.
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role of Vaspin in human eating behaviour
PLOS ONE, 2013Co-Authors: Jana Breitfeld, Peter Kovacs, Michael Stumvoll, Matthias Bluher, Anke Tonjes, Dorit Schleinitz, Marietherese Gast, Yvonne BöttcherAbstract:Objective The adipokine Vaspin (visceral adipose tissue derived serine protease inhibitor, serpinA12) follows a meal-related diurnal variation in humans and intracerebroventricular Vaspin administration leads to acutely reduced food intake in db/db mice. We therefore hypothesized that Vaspin may play a role in human eating behaviour.
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insulin administration acutely decreases Vaspin serum concentrations in humans
Obesity Facts, 2013Co-Authors: Peter Kovacs, Michael Stumvoll, Konstanze Miehle, Benjamin Sandner, Matthias BluherAbstract:It has been hypothesized that insulin might mediate meal-related diurnal variation in Vaspin serum concentrations. We therefore investigated whether insulin affects serum Vaspin levels in humans. Vaspin serum concentrations were determined by ELISA in 10 healthy individuals, who underwent an insulin tolerance test (ITT) for the evaluation of pituitary ACTH and growth hormone reserve. The ITTs were started 08:00 am after an overnight fast with a bolus i.v. insulin dose of 0.15 IU/kg body weight (Actrapid). Blood samples were taken at -15, 0, 15, 30, 60, 90, and 120 min after insulin administration. 15 min after insulin administration, Vaspin serum concentrations decreased by 19 ± 6%, continued to decrease by 42 ± 12% at 60 min and returned to 88 ± 7% of initial values 120 min after insulin administration. Our data suggest that meal-related changes in serum Vaspin concentrations might be mediated by insulin.
Michael Stumvoll - One of the best experts on this subject based on the ideXlab platform.
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circulating adipokine Vaspin is associated with serum lipid profiles in humans
Lipids, 2019Co-Authors: Jana Breitfeld, Peter Kovacs, Michael Stumvoll, Matthias Bluher, Norman Wiele, Beate Gutsmann, Markus Scholz, Anke TonjesAbstract:Vaspin, visceral adipose tissue-derived serpin, is an adipokine ameliorating insulin resistance in obesity. Here, we investigated the role of Vaspin and its genetic variants in lipid metabolism. We measured serum Vaspin concentrations by ELISA in 823 metabolically well-characterized Caucasian subjects (Sorbs from Germany). Furthermore, we genotyped 30 representative single nucleotide polymorphisms (SNP) in two independent cohorts with metabolic phenotyping, the Sorbs (N = 823) and Leipzig (N = 919), and conducted genotype-phenotype association analyses. Circulating Vaspin strongly correlated with triacylglycerol levels (TAG; p = 1.079 × 10-11 ), and moderately with apolipoprotein A1 and low-density lipoprotein cholesterol (p = 0.026). Genetic variants in Vaspin were nominally associated with cholesterol, high-density and low-density lipoprotein (HDL-chol, LDL-chol), lipoprotein A, and apolipoprotein B as well as with TAG and free fatty acids (all p < 0.05 adjusted for age, sex, and body mass index [BMI]). Mendelian randomization analysis using Vaspin SNP as an instrumental variable showed borderline influence of Vaspin on LDL-chol levels (p = 0.05). Associations of Vaspin and its genetic variation with metabolic traits suggest a role of Vaspin in human lipid metabolism.
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Brown adipose tissue (BAT) specific Vaspin expression is increased after obesogenic diets and cold exposure and linked to acute changes in DNA-methylation.
Molecular metabolism, 2017Co-Authors: Juliane Weiner, Nora Kloting, Peter Kovacs, Michael Stumvoll, Matthias Bluher, Kerstin Rohde, Kerstin Krause, Konstanze Zieger, Susan Kralisch, Yvonne BöttcherAbstract:Abstract Objective Several studies have demonstrated anti-diabetic and anti-obesogenic properties of visceral adipose tissue-derived serine protease inhibitor (Vaspin) and so evoked its potential use for treatment of obesity-related diseases. The aim of the study was to unravel physiological regulators of Vaspin expression and secretion with a particular focus on its role in brown adipose tissue (BAT) biology. Methods We analyzed the effects of obesogenic diets and cold exposure on Vaspin expression in liver and white and brown adipose tissue (AT) and plasma levels. Vaspin expression was analyzed in isolated white and brown adipocytes during adipogenesis and in response to adrenergic stimuli. DNA-methylation within the Vaspin promoter was analyzed to investigate acute epigenetic changes after cold-exposure in BAT. Results Our results demonstrate a strong induction of Vaspin mRNA and protein expression specifically in BAT of both cold-exposed and high-fat (HF) or high-sugar (HS) fed mice. While obesogenic diets also upregulated hepatic Vaspin mRNA levels, cold exposure tended to increase Vaspin gene expression of inguinal white adipose tissue (iWAT) depots. Concomitantly, Vaspin plasma levels were decreased upon obesogenic or thermogenic triggers. Vaspin expression was increased during adipogenesis but unaffected by sympathetic activation in brown adipocytes. Analysis of Vaspin promoter methylation in AT revealed lowest methylation levels in BAT, which were acutely reduced after cold exposure. Conclusions Our data demonstrate a novel BAT-specific regulation of Vaspin gene expression upon physiological stimuli in vivo with acute epigenetic changes that may contribute to cold-induced expression in BAT. We conclude that these findings indicate functional relevance and potentially beneficial effects of Vaspin in BAT function.
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Vaspin inhibits kallikrein 7 by serpin mechanism
Cellular and Molecular Life Sciences, 2013Co-Authors: John T Heiker, Nora Kloting, Peter Kovacs, Bartholomeus E Kuettner, Norbert Strater, S Schultz, Matthias Kern, Michael Stumvoll, Matthias Bluher, Annette G BecksickingerAbstract:The molecular target of the adipokine Vaspin (visceral adipose tissue-derived serpin; serpinA12) and its mode of action are unknown. Here, we provide the Vaspin crystal structure and identify human kallikrein 7 (hK7) as a first protease target of Vaspin inhibited by classical serpin mechanism with high specificity in vitro. We detect Vaspin–hK7 complexes in human plasma and find co-expression of both proteins in murine pancreatic β-cells. We further demonstrate that hK7 cleaves human insulin in the A- and B-chain. Vaspin treatment of isolated pancreatic islets leads to increased insulin concentration in the media upon glucose stimulation without influencing insulin secretion. By application of Vaspin and generated inactive mutants, we find the significantly improved glucose tolerance in C57BL/6NTac and db/db mice treated with recombinant Vaspin fully dependent on the Vaspin serpin activity and not related to Vaspin-mediated changes in insulin sensitivity as determined by euglycemic-hyperinsulinemic clamp studies. Improved glucose metabolism could be mediated by increased insulin plasma concentrations 150 min after a glucose challenge in db/db mice, supporting the hypothesis that Vaspin may inhibit insulin degradation by hK7 in the circulation. In conclusion, we demonstrate the inhibitory serpin nature and the first protease target of the adipose tissue-derived serpin Vaspin, and our findings suggest hK7 inhibition by Vaspin as an underlying physiological mechanism for its compensatory actions on obesity-induced insulin resistance.
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role of Vaspin in human eating behaviour
PLOS ONE, 2013Co-Authors: Jana Breitfeld, Peter Kovacs, Michael Stumvoll, Matthias Bluher, Anke Tonjes, Dorit Schleinitz, Marietherese Gast, Yvonne BöttcherAbstract:Objective The adipokine Vaspin (visceral adipose tissue derived serine protease inhibitor, serpinA12) follows a meal-related diurnal variation in humans and intracerebroventricular Vaspin administration leads to acutely reduced food intake in db/db mice. We therefore hypothesized that Vaspin may play a role in human eating behaviour.
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insulin administration acutely decreases Vaspin serum concentrations in humans
Obesity Facts, 2013Co-Authors: Peter Kovacs, Michael Stumvoll, Konstanze Miehle, Benjamin Sandner, Matthias BluherAbstract:It has been hypothesized that insulin might mediate meal-related diurnal variation in Vaspin serum concentrations. We therefore investigated whether insulin affects serum Vaspin levels in humans. Vaspin serum concentrations were determined by ELISA in 10 healthy individuals, who underwent an insulin tolerance test (ITT) for the evaluation of pituitary ACTH and growth hormone reserve. The ITTs were started 08:00 am after an overnight fast with a bolus i.v. insulin dose of 0.15 IU/kg body weight (Actrapid). Blood samples were taken at -15, 0, 15, 30, 60, 90, and 120 min after insulin administration. 15 min after insulin administration, Vaspin serum concentrations decreased by 19 ± 6%, continued to decrease by 42 ± 12% at 60 min and returned to 88 ± 7% of initial values 120 min after insulin administration. Our data suggest that meal-related changes in serum Vaspin concentrations might be mediated by insulin.
Akihiro Katayama - One of the best experts on this subject based on the ideXlab platform.
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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
Circulation Research, 2013Co-Authors: Atsuko Nakatsuka, Jun Wada, Izumi Iseda, Sanae Teshigawara, Kanji Higashio, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro KatayamaAbstract: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 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.
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Vaspin is an adipokine ameliorating er stress in obesity as a ligand for cell surface grp78 mtj 1 complex
Diabetes, 2012Co-Authors: Atsuko Nakatsuka, Jun Wada, Izumi Iseda, Sanae Teshigawara, Kanji Higashio, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro KatayamaAbstract:It is unknown whether adipokines derived from adipose tissues modulate endoplasmic reticulum (ER) stress induced in obesity. Here, we show that visceral adipose tissue–derived serine protease inhibitor (Vaspin) binds to cell-surface 78-kDa glucose-regulated protein (GRP78), which is recruited from ER to plasma membrane under ER stress. Vaspin transgenic mice were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis, while Vaspin-deficient mice developed glucose intolerance associated with upregulation of ER stress markers. With tandem affinity tag purification using HepG2 cells, we identified GRP78 as an interacting molecule. The complex formation of Vaspin, GRP78, and murine tumor cell DnaJ-like protein 1 (MTJ-1) (DnaJ homolog, subfamily C, member 1) on plasma membrane was confirmed by cell-surface labeling with biotin and immunoprecipitation in liver tissues and H-4-II-E-C3 cells. The addition of recombinant human Vaspin in the cultured H-4-II-E-C3 cells also increased the phosphorylation of Akt and AMP-activated protein kinase (AMPK) in a dose-dependent manner, and anti-GRP78 antibodies completely abrogated the Vaspin-induced upregulation of pAkt and pAMPK. Vaspin is a novel ligand for cell-surface GRP78/MTJ-1 complex, and its subsequent signals exert beneficial effects on ER stress–induced metabolic dysfunctions.
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serum Vaspin concentrations are closely related to insulin resistance and rs77060950 at serpina12 genetically defines distinct group with higher serum levels in japanese population
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Sanae Teshigawara, Atsuko Nakatsuka, Jun Eguchi, Jun Wada, Kazuyuki Hida, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro KatayamaAbstract:Context: Vaspin is an adipokine with insulin-sensitizing effects identified from visceral adipose tissues of genetically obese rats. Objective: We investigated genetic and nongenetic factors that define serum concentrations of Vaspin. Design, Setting and Participants: Vaspin levels were measured with RIA in Japanese subjects with normal fasting plasma glucose (NFG; n = 259) and type 2 diabetes patients (T2D; n = 275). Single nucleotide polymorphisms (SNP) at SERPINA12 (Vaspin) gene locus were discovered, and five SNP were genotyped in the subjects with varied body mass index (n = 1138). Results: The level of serum Vaspin in 93% of the samples was found to vary from 0.2 to nearly 2 ng/ml in NFG subjects (n = 259) and from 0.2 to nearly 3 ng/ml in T2D patients (n = 275) (Vaspin(Low) group), whereas a significant subpopulation (7%) in both groups displayed much higher levels of 10-40 ng/ml (Vaspin(High) group). In the Vaspin(Low) group, serum Vaspin levels in T2D were significantly higher than healthy subjects (0.99 +/- 0.04 vs. 0.86 +/- 0.02 ng/ml; P < 0.01). Both in T2D and genotyped Japanese population, serum Vaspin levels closely correlated with homeostasis model of assessment for insulin resistance rather than anthropometric parameters. By genotyping, rs77060950 tightly linked to serum Vaspin levels, i.e. CC (0.6 +/- 0.4 ng/ml), CA (18.4 +/- 9.6 ng/ml), and AA (30.5 +/- 5.1 ng/ml) (P < 2 x 10(-16)). Putative GATA-2 and GATA-3 binding consensus site was found at rs77060950. Conclusions: Serum Vaspin levels were related to insulin resistance, and higher levels of serum Vaspin in 7% of the Japanese population are closely linked to minor allele sequence (A) of rs77060950. (J Clin Endocrinol Metab 97: E1202-E1207, 2012)
Jun Wada - One of the best experts on this subject based on the ideXlab platform.
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a Vaspin hspa1l complex protects proximal tubular cells from organelle stress in diabetic kidney disease
Communications Biology, 2021Co-Authors: Atsuko Nakatsuka, Satoshi Yamaguchi, Jun Eguchi, Shigeru Kakuta, Yoichiro Iwakura, Hitoshi Sugiyama, Jun WadaAbstract:Proximal tubular cells (PTCs) are crucial for maintaining renal homeostasis, and tubular injuries contribute to progression of diabetic kidney disease (DKD). However, the roles of visceral adipose tissue-derived serine protease inhibitor (Vaspin) in the development of DKD is not known. We found Vaspin maintains PTCs through ameliorating ER stress, autophagy impairment, and lysosome dysfunction in DKD. Vaspin−/− obese mice showed enlarged and leaky lysosomes in PTCs associated with increased apoptosis, and these abnormalities were also observed in the patients with DKD. During internalization into PTCs, Vaspin formed a complex with heat shock protein family A (Hsp70) member 1 like (HSPA1L) as well as 78 kDa glucose-regulated protein (GRP78). Both Vaspin-partners bind to clathrin heavy chain and involve in the endocytosis. Notably, albumin-overload enhanced extracellular release of HSPA1L and overexpression of HSPA1L dissolved organelle stresses, especially autophagy impairment. Thus, vapsin/HSPA1L-mediated pathways play critical roles in maintaining organellar function of PTCs in DKD. Nakatsuka et al. discover that the adipokine Vaspin contributes to maintaining proximal tubular cell (PTC) homeostasis by ameliorating organelle stress. They find that upon internalization, Vaspin interacts with the heat shock protein HSPA1L and that the proteins cooperate to prevent metabolic stress-induced cellular injuries in PTCs.
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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
Circulation Research, 2013Co-Authors: Atsuko Nakatsuka, Jun Wada, Izumi Iseda, Sanae Teshigawara, Kanji Higashio, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro KatayamaAbstract: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 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.
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the serum Vaspin levels are reduced in japanese chronic hemodialysis patients
BMC Nephrology, 2012Co-Authors: Junko Inoue, Atsuko Nakatsuka, Jun Wada, Kazuyuki Hida, Sanae Teshigawara, Yuji Takatori, Shoichirou Kojo, Shigeru Akagi, Kazushi Nakao, Nobuyuki MiyatakeAbstract:Background Visceral adipose tissue-derived serine proteinase inhibitor (Vaspin) is an adipokine identified in genetically obese rats that correlates with insulin resistance and obesity in humans. Recently, we found that 7% of the Japanese population with the minor allele sequence (A) of rs77060950 exhibit higher levels of serum Vaspin. We therefore evaluated the serum Vaspin levels in Japanese chronic hemodialysis patients.
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Vaspin is an adipokine ameliorating er stress in obesity as a ligand for cell surface grp78 mtj 1 complex
Diabetes, 2012Co-Authors: Atsuko Nakatsuka, Jun Wada, Izumi Iseda, Sanae Teshigawara, Kanji Higashio, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro KatayamaAbstract:It is unknown whether adipokines derived from adipose tissues modulate endoplasmic reticulum (ER) stress induced in obesity. Here, we show that visceral adipose tissue–derived serine protease inhibitor (Vaspin) binds to cell-surface 78-kDa glucose-regulated protein (GRP78), which is recruited from ER to plasma membrane under ER stress. Vaspin transgenic mice were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis, while Vaspin-deficient mice developed glucose intolerance associated with upregulation of ER stress markers. With tandem affinity tag purification using HepG2 cells, we identified GRP78 as an interacting molecule. The complex formation of Vaspin, GRP78, and murine tumor cell DnaJ-like protein 1 (MTJ-1) (DnaJ homolog, subfamily C, member 1) on plasma membrane was confirmed by cell-surface labeling with biotin and immunoprecipitation in liver tissues and H-4-II-E-C3 cells. The addition of recombinant human Vaspin in the cultured H-4-II-E-C3 cells also increased the phosphorylation of Akt and AMP-activated protein kinase (AMPK) in a dose-dependent manner, and anti-GRP78 antibodies completely abrogated the Vaspin-induced upregulation of pAkt and pAMPK. Vaspin is a novel ligand for cell-surface GRP78/MTJ-1 complex, and its subsequent signals exert beneficial effects on ER stress–induced metabolic dysfunctions.
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serum Vaspin concentrations are closely related to insulin resistance and rs77060950 at serpina12 genetically defines distinct group with higher serum levels in japanese population
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Sanae Teshigawara, Atsuko Nakatsuka, Jun Eguchi, Jun Wada, Kazuyuki Hida, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro KatayamaAbstract:Context: Vaspin is an adipokine with insulin-sensitizing effects identified from visceral adipose tissues of genetically obese rats. Objective: We investigated genetic and nongenetic factors that define serum concentrations of Vaspin. Design, Setting and Participants: Vaspin levels were measured with RIA in Japanese subjects with normal fasting plasma glucose (NFG; n = 259) and type 2 diabetes patients (T2D; n = 275). Single nucleotide polymorphisms (SNP) at SERPINA12 (Vaspin) gene locus were discovered, and five SNP were genotyped in the subjects with varied body mass index (n = 1138). Results: The level of serum Vaspin in 93% of the samples was found to vary from 0.2 to nearly 2 ng/ml in NFG subjects (n = 259) and from 0.2 to nearly 3 ng/ml in T2D patients (n = 275) (Vaspin(Low) group), whereas a significant subpopulation (7%) in both groups displayed much higher levels of 10-40 ng/ml (Vaspin(High) group). In the Vaspin(Low) group, serum Vaspin levels in T2D were significantly higher than healthy subjects (0.99 +/- 0.04 vs. 0.86 +/- 0.02 ng/ml; P < 0.01). Both in T2D and genotyped Japanese population, serum Vaspin levels closely correlated with homeostasis model of assessment for insulin resistance rather than anthropometric parameters. By genotyping, rs77060950 tightly linked to serum Vaspin levels, i.e. CC (0.6 +/- 0.4 ng/ml), CA (18.4 +/- 9.6 ng/ml), and AA (30.5 +/- 5.1 ng/ml) (P < 2 x 10(-16)). Putative GATA-2 and GATA-3 binding consensus site was found at rs77060950. Conclusions: Serum Vaspin levels were related to insulin resistance, and higher levels of serum Vaspin in 7% of the Japanese population are closely linked to minor allele sequence (A) of rs77060950. (J Clin Endocrinol Metab 97: E1202-E1207, 2012)
