Vaspin inhibits kallikrein 7 by serpin mechanism

Heiker, John T.; Klöting, Nora; Kovacs, Peter; Kuettner, E.B.; Sträter, Norbert; Schultz, Stephan; Kern, Matthias; Stümvoll, Michael; Blüher, Matthias; Beck‐Sickinger, Annette G.

doi:10.1007/s00018-013-1258-8

Cited by 135 publications

(160 citation statements)

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“…Insulin-resistant mouse models exhibit improved glucose tolerance after intraperitoneal vaspin application (3,4), and transgenic mice overexpressing vaspin are protected from diet-induced obesity and comorbidities, such as glucose intolerance, insulin resistance, and adipose tissue inflammation (5). We found that intraperitoneal and central administration of vaspin leads to reduced food intake and blood glucose in mice (6).…”

mentioning

confidence: 82%

“…KLK7 also cleaves recombinant vaspin after Tyr 30 , resulting in loss of the N-terminal His tag and vaspin residues Lys 22 -Tyr 30 (4). We therefore used the R302E mutant, which due to the negative charge at the exosite for KLK7 is not cleaved within the RCL, but only at the N terminus.…”

Section: Role Of N-terminal Basic Residues In Heparinmentioning

confidence: 99%

“…In skin, vaspin expression by keratinocytes suppresses the expression and release of inflammatory cytokines by immune cells (11) and possibly regulates the activation of proinflammatory cytokines, such as chemerin, via KLK7 (12). Whereas vaspin-mediated improvement of glucose tolerance and reduction of food intake were found to be dependent on protease inhibition (4,13), anti-inflammatory effects in the liver have been linked to interaction with a membrane-associated endoplasmic reticulum chaperone protein (5).…”

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confidence: 99%

“…A non-inhibitory vaspin mutant failed to improve glucose tolerance in obese mice, proving that protease inhibition is a prerequisite for vaspin effects on glucose disposal (4). Human insulin is a substrate of KLK7, and vaspin and KLK7 are co-expressed in murine pancreatic islets.…”

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confidence: 99%

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Basic Residues of β-Sheet A Contribute to Heparin Binding and Activation of Vaspin (Serpin A12)

Ulbricht

Oertwig

Arnsburg

et al. 2017

Journal of Biological Chemistry

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Vaspin (serpin A12) was identified in adipose tissue of the OLETF rat type-2 diabetes model and functions as an antidiabetic and anti-atherogenic adipokine in obesity-related disorders, such as insulin resistance and inflammation (1, 2). Insulin-resistant mouse models exhibit improved glucose tolerance after intraperitoneal vaspin application (3, 4), and transgenic mice overexpressing vaspin are protected from diet-induced obesity and comorbidities, such as glucose intolerance, insulin resistance, and adipose tissue inflammation (5). We found that intraperitoneal and central administration of vaspin leads to reduced food intake and blood glucose in mice (6). A recent study demonstrated that central vaspin regulates hepatic glucose production and insulin signaling via brain-liver communication through the dorsal vagal complex (7). In endothelial and vascular smooth muscle cells, multiple studies demonstrated anti-apoptotic (8), anti-inflammatory (9), and anti-migratory (10) effects of vaspin, suggesting a protective role in the pathogenesis of atherosclerosis. In skin, vaspin expression by keratinocytes suppresses the expression and release of inflammatory cytokines by immune cells (11) and possibly regulates the activation of proinflammatory cytokines, such as chemerin, via KLK7 (12). Whereas vaspin-mediated improvement of glucose tolerance and reduction of food intake were found to be dependent on protease inhibition (4, 13), anti-inflammatory effects in the liver have been linked to interaction with a membrane-associated endoplasmic reticulum chaperone protein (5).The only protease target of vaspin known so far is human KLK7 (4), a member of a family of 15 serine peptidases with chymotrypsin-like specificity (14). A non-inhibitory vaspin mutant failed to improve glucose tolerance in obese mice, proving that protease inhibition is a prerequisite for vaspin effects on glucose disposal (4). Human insulin is a substrate of KLK7, and vaspin and KLK7 are co-expressed in murine pancreatic islets. We hypothesized that KLK7 inhibition by vaspin may prolong insulin action and increase glucose uptake in insulinresponsive tissues, such as adipose tissue, liver, muscle, and also brain.We have recently reported that the inhibition of KLK7 by vaspin is critically dependent on an arginine residue in proximity to the reactive center loop (RCL), 2 because the native P1Ј glutamate residue is essentially repressing inhibition of KLK7 (15). Inhibition of KLK7 by vaspin is furthermore accelerated by heparin (15). Yet, the nature of the interaction between glycosaminoglycans and vaspin has not been explored in much detail.

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confidence: 82%

Section: Role Of N-terminal Basic Residues In Heparinmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Basic Residues of β-Sheet A Contribute to Heparin Binding and Activation of Vaspin (Serpin A12)

Ulbricht

Oertwig

Arnsburg

et al. 2017

Journal of Biological Chemistry

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“…12 This beneficial effect has been related by Heiker et al to inhibition of kallikrein 7 by vaspin, which is a member of serine protease inhibitor family. 13 There is possibility that vaspin has compensatory effect in insulin resistance. Besides, there is a potential correlation of vaspin with the chronic inflammation in the diabetic patients.…”

Section: Introductionmentioning

confidence: 99%

The correlation of inflammatory markers and plasma vaspin levels in patients with diabetic nephropathy

et al. 2016

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Vaspin, a recently identified adipokine, is a visceral adipose tissue-derived serine protease inhibitor that may have insulin sensitizing effect on adipose tissue. Herein, we measured vaspin level in patients with different stages of diabetic nephropathy (DNP), and investigated the correlation of the vaspin level with other inflammatory parameters. 106 adult type 2 diabetic patients with no known chronic inflammatory disease were included and grouped according to the stage of DNP: Albuminuria <30 mg/day and estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73m 2 (Group-1); albuminuria 30-300 mg/day and eGFR >60 mL/min/1.73m 2 (Group-2); albuminuria >300 mL/min and eGFR <60 mL/min/1.73m 2 (Group-3). Demographic, clinical and laboratory data were recorded as well as vaspin, high sensitivity C-reactive protein (hsCRP), interleukin (IL)-1 and tumor necrosis factor (TNF)-a levels. There were 38, 35 and 33 patients in Group 1, 2 and 3, respectively. Groups were similar regarding age and gender. Vaspin level did not differ between groups. When all the groups were considered, vaspin was positively correlated with IL-6 level (r ¼ 0.215, p ¼ 0.041). No correlation of vaspin was found with IL-1, TNF-a and hsCRP levels (p ¼ 0.580, r ¼ 0.054; p ¼ 0.463, r ¼ 0.072; p ¼ 0.812, r ¼ 0.025, respectively). Vaspin levels of the patients with GFR !60 mL/min/1.73m 2 was less than that of patients with GFR <60 mL/min/ 1.73m 2 (p ¼ 0.03). Age and IL-6 were found to be the major determinants of vaspin level with linear regression analysis. In patients with DNP, vaspin level does not change within the early stages of DNP; while it is higher in patients with decreased GFR, which may be related with increasing inflammation regardless of the stage of the kidney disease.ARTICLE HISTORY

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Inhibition of Kallikrein‐Related Peptidases 7 and 5 by Grafting Serpin Reactive‐Center Loop Sequences onto Sunflower Trypsin Inhibitor‐1 (SFTI‐1)

Jendrny

Beck‐Sickinger

2015

ChemBioChem

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Serpin proteins irreversibly inhibit serine proteases, but only a small part of the serpin reactive-center loop (RCL) is responsible for the initial protein-protein interaction (PPI). To develop peptidic protease inhibitors, kallikrein-related peptidases 7 (KLK7) and 5 (KLK5) were chosen. Firstly, we demonstrated that short peptides derived from RCL sequences can be cleaved by KLK7 in a substrate-like manner. Next, these substrates were grafted onto the protease-binding loop of sunflower trypsin inhibitor-1 (SFTI-1). Peptides based on kallistatin, α1 -antichymotrypsin, and protein C inhibitor (PCI) inhibited KLK7 with Ki =0.4, 0.5, and 0.7 μm, respectively. In contrast, the trypsin-like KLK5 was only blocked by the peptide derived from PCI (Ki =0.6 μm). Thus, serpin function can be mimicked by introducing its PPI site into the rigid structure of the SFTI-1 scaffold. This approach might be applicable not only to KLKs but also to other serine protease members, thus opening up new therapeutic fields.

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Vaspin inhibits kallikrein 7 by serpin mechanism

Cited by 135 publications

References 57 publications

Basic Residues of β-Sheet A Contribute to Heparin Binding and Activation of Vaspin (Serpin A12)

Basic Residues of β-Sheet A Contribute to Heparin Binding and Activation of Vaspin (Serpin A12)

The correlation of inflammatory markers and plasma vaspin levels in patients with diabetic nephropathy

Inhibition of Kallikrein‐Related Peptidases 7 and 5 by Grafting Serpin Reactive‐Center Loop Sequences onto Sunflower Trypsin Inhibitor‐1 (SFTI‐1)

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