Inhibition of dipeptidyl peptidase 4 regulates microvascular endothelial growth induced by inflammatory cytokines

Takasawa, Wataru; Ohnuma, Kei; Hatano, Ryo; Endo, Yuko; Dang, Nam H.; Morimoto, Chikao

doi:10.1016/j.bbrc.2010.08.112

Cited by 59 publications

(41 citation statements)

References 25 publications

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“…Several mechanisms, have been proposed to explain such beneficial effects on lipid profile by DPP4i other than improving glycemic control such as GLP-1 induced myocardial protection [40], improving endothelial function [41], and even having an antiinflammatory role by reducing C-reactive protein levels [42].…”

Section: Discussionmentioning

confidence: 99%

Theeffect of Dipeptidyl Peptidase-4 Inhibitors on Cardiovascular Disease Risk in Type 2 Diabetes Mellitus

Tolba

Khashab

Said

2016

Int J Pharm Pharm Sci

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Objective: The aim of this study was is to investigate the proposed beneficial cardiovascular effects of a novel class of antidiabetic drugs named; dipeptidyl peptidase 4 inhibitors. In this study, we compared the effect of using add-on therapy of vildagliptin (dipeptidyl peptidase-4 inhibitor; DPP-4i) and gliclazide (sulphonylurea; SU) to that when using gliclazide monotherapy in patients with type 2 diabetes mellitus (T2DM) and acute coronary syndrome (ACS) on different cardiovascular outcomes.Methods: A total of 60 patients diagnosed with T2DM, and ACS were randomly recruited into two treatment groups each of 30 patients to receive either gliclazide monotherapy (SU) or vildagliptin (DPP4i)+gliclazide (SU) add-on therapy, administered in a double-blind fashion. Outpatient visits were scheduled at 3, 6, and 12 mo where patient was reevaluated for cardiovascular (CV) outcomes and followed up for any arising cardiovascular complication. Results:The vildagliptin (DPP4i) plus gliclazide (SU) add-on therapy group have significantly shown more improved glycemic control, lipid profile and ventricular performance compared to gliclazide (SU) monotherapy group with p values<0.05. Conclusion:Vildagliptin as a DPP4i provides favourable cardiovascular effects beyond glucose control. Yet, its long-term safety and efficacy data still needs further investigations.

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Section: Discussionmentioning

confidence: 99%

Theeffect of Dipeptidyl Peptidase-4 Inhibitors on Cardiovascular Disease Risk in Type 2 Diabetes Mellitus

Tolba

Khashab

Said

2016

Int J Pharm Pharm Sci

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“…In the dermis, CD26 was predominantly expressed by fibroblasts and not by blood vessel endothelial cells (Takasawa et al, 2010) or CD45-positive bone marrow-derived cells. CD26 activity in cultured fibroblasts was stimulated by treatment with IL-1a (Nemoto et al, 1999).…”

Section: Discussionmentioning

confidence: 92%

“…Although in some contexts CD26 is expressed by endothelial cells (Takasawa et al, 2010), CD26 was not expressed by CD31-positive blood vessels in WT and InvEE skin or InvEE tumour stroma (Figure 4c). In WT and InvEE skin, most bone marrowderived (CD45-positive) cells lacked CD26; however, in InvEE tumours the few CD26-positive cells in the stroma were CD45 positive (Figure 4d).…”

Section: Cd26 Expression By Differentiated Epidermal Cellsmentioning

confidence: 98%

“…One protein was significantly upregulated in InvEE epidermis: CD26 (Figure 1a). CD26/DPPIV is a dipeptidyl peptidase expressed on the surface of several cell types, including epithelial cells, fibroblasts, endothelial cells and activated immune cells (Ohnuma et al, 2008;Takasawa et al, 2010). CD26 is primarily associated with immune regulation, via enzymatic cleavage of cytokines, and with T cell activation (Ohnuma et al, 2008).…”

Section: Elevated Cd26 Levels and Activity In Invee Epidermismentioning

confidence: 99%

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Upregulation of CD26 expression in epithelial cells and stromal cells during wound-induced skin tumour formation

et al. 2011

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We have previously described InvEE transgenic mice in which non-dividing, differentiating epidermal cells express oncogenically activated MAPK kinase 1 (MEK1). Skin wounding triggers tumour formation in InvEE mice via a mechanism that involves epidermal release of IL-1a and attraction of a pro-tumorigenic inflammatory infiltrate. To look for potential effects on the underlying connective tissue, we screened InvEE and wild-type epidermis for differential expression of cytokines and immune modulators. We identified a single protein, CD26 (dipeptidyl peptidase-4). CD26 serum levels were not increased in InvEE mice. In contrast, CD26 was upregulated in keratinocytes expressing mutant MEK1 and in the epithelial compartment of InvEE tumours, where it accumulated at cell-cell borders. CD26 expression was increased in dermal fibroblasts following skin wounding but was downregulated in tumour stroma. CD26 activity was stimulated by calcium-induced intercellular adhesion in keratinocytes, suggesting that the upregulation of CD26 in InvEE epidermis is due to expansion of the differentiated cell layers. IL-1a treatment of dermal fibroblasts stimulated CD26 activity, and therefore epidermal IL-1a release may contribute to the upregulation of CD26 expression in wounded dermis. Pharmacological blockade of CD26, via Sitagliptin, reduced growth of InvEE tumours, while combined inhibition of IL-1a and CD26 delayed tumour onset and reduced tumour incidence. Our results demonstrate that inappropriate activation of MEK1 in the epidermis leads to changes in dermal fibroblasts that, like the skin inflammatory infiltrate, contribute to tumour formation.

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“…Vascular inflammation is a key feature of diabetic micro-and macrovascular complications. It has been clearly demonstrated that expression of CD26 in human microvascular endothelial cells is suppressed by proinflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin-1β, and that pharmacological inhibition of enzymatic activity of CD26/DPPIV is directly associated with endothelial proliferation and migration and neovascularization in the inflammatory setting [8]. Experimental findings and preliminary clinical data suggest that the inhibitors can ameliorate diabetic microangiopathy.…”

Section: Humanized Anti-cd26 Monoclonal Antibody (Ys110) For the Treamentioning

confidence: 99%

Possible new therapeutic agents for malignant pleural mesothelioma: anti-CD26 monoclonal antibody and naftopidil

Nakano

Kuribayashi

Mikami

2016

Expert Review of Anticancer Therapy

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Inhibition of dipeptidyl peptidase 4 regulates microvascular endothelial growth induced by inflammatory cytokines

Cited by 59 publications

References 25 publications

Theeffect of Dipeptidyl Peptidase-4 Inhibitors on Cardiovascular Disease Risk in Type 2 Diabetes Mellitus

Theeffect of Dipeptidyl Peptidase-4 Inhibitors on Cardiovascular Disease Risk in Type 2 Diabetes Mellitus

Upregulation of CD26 expression in epithelial cells and stromal cells during wound-induced skin tumour formation

Possible new therapeutic agents for malignant pleural mesothelioma: anti-CD26 monoclonal antibody and naftopidil

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