Dipeptidyl peptidase-4 inhibition by gemigliptin prevents abnormal vascular remodeling via NF-E2-related factor 2 activation

Choi, Seung Hee; Park, Sungmi; Oh, Chang Joo; Leem, Jaechan; Park, Keun-Gyu; Lee, Inkyu

doi:10.1016/j.vph.2015.07.005

Cited by 51 publications

(35 citation statements)

References 43 publications

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“…On the other hand, sitagliptin pretreatment increased the expression of Nrf2 and increased its binding activity. This finding is in harmony with the recent study of Choi et al [26] which reported the ability of gemigliptin, another DDP4 inhibitor, to exert protective vascular effects via enhancement of Nrf2 activity. The plausible mechanism for sitagliptin on Nrf2 might explain sitagliptin ability to increase SOD activity leading to enhancement of the antioxidant defense status of the liver and hence amelioration of oxidative stress.…”

Section: Discussionsupporting

confidence: 90%

Hepatoprotective effect of sitagliptin against methotrexate induced liver toxicity

et al. 2017

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Sitagliptin is selective dipeptidyl peptidase-4 inhibitor (DPP4-I), used clinically as a new oral anti-diabetic agent. This study explored the underlying mechanisms of the hepatoprotective role of sitagliptin pretreatment against methotrexate (MTX) induced hepatotoxicity in mice. Forty mice were divided into four groups (10 mice each); control, MTX, and two sitagliptin groups (pretreated with sitagliptin 10 and 20 mg/kg/day, respectively) for five consecutive days prior to MTX injection. Results showed that MTX induced marked hepatic injury in the form of cloudy swelling, hydropic degeneration, apoptosis and focal necrosis in all hepatic zones. Biochemical analysis revealed significant increase in the serum transaminases, alkaline phosphatase and lactate dehydrogenase in MTX group. Oxidative stress and depressed antioxidant system of the hepatic tissues were evident in MTX group. MTX down-regulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and reduced its binding capacity. Additionally, MTX increased the activation and the expression of nuclear factor kappa-B (NF-κB) and downstream inflammatory mediators. MTX induced the activation of inducible nitric oxide synthase (iNOS) and increased nitrite/nitrate level. Finally, hepatic cellular apoptosis was clearly obvious in MTX-intoxicated animals using TUNEL staining. Also, there was increase in the immunoexpression of pro-apoptotic protein Bax, increase in Bax and caspase-3 levels and decrease in the level of anti-apoptotic Bcl2 in liver. On the other hand, sitagliptin pretreatment significantly ameliorated all of the above mentioned biochemical, histopathological, immunohistochemical changes induced by MTX. These results provide new evidences that the hepatoprotective effect of sitagliptin is possibly mediated through modulation of Nrf2 and NF-κB signaling pathways with subsequent suppression of inflammatory and apoptotic processes.

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Section: Discussionsupporting

confidence: 90%

Hepatoprotective effect of sitagliptin against methotrexate induced liver toxicity

et al. 2017

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“…As shown by others (13) VSMCs (12). Even if the exact signalling pathways that translate DPP-4 inhibition into cellular effects remain obscure, these new data confirm that DPP-4i has the potential to favourably affect the vasculature and protect from cardiovascular disease.…”

Section: Basic Evidencesupporting

confidence: 67%

“…In Though the question of whether soluble or membrane-bound cell-derived DPP-4 was involved remains unanswered, data suggest that DPP-4i triggered intracellular events, including enhancement of NF-E2-related factor 2 (Nrf2) activity, culminating in a reduction of VSMC migration and proliferation (12). As shown by others (13) VSMCs (12).…”

Section: Basic Evidencementioning

confidence: 98%

“…A detailed review of the cardiovascular actions of incretin-based therapies can be found elsewhere (10). In this issue of Vascular Pharmacology, Choi et al report that the DPP-4i gemigliptin prevented migration and proliferation of vascular smooth muscle cells (VSMCs) in vitro and attenuated neointimal hyperplasia in ligated mouse carotid arteries in vivo(12). The in vitro activity of gemigliptin was mimicked by DPP-4 siRNA-mediated knockdown, suggesting that VSMC-derived DPP-4 regulates proliferation.…”

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confidence: 99%

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Direct effects of DPP-4 inhibition on the vasculature. Reconciling basic evidence with lack of clinical evidence

Fadini

Albiero

Avogaro

2015

Vascular Pharmacology

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“…Anti‐inflammatory cardiovascular and renal effects of gemigliptin were reported to be achieved in vitro and in vivo. In vitro this gliptin exerted protective effects in rat vascular smooth muscle cells, rat cardiomyocytes, rat mesangial, and kidney proximal tubular epithelial cells . In mice gemigliptin reduced proliferation of vascular smooth muscle cells .…”

Section: Suppression Of Inflammatory Mediators and Pathways In Vasculmentioning

confidence: 88%

Mechanisms and pathways of anti‐inflammatory activity of DPP‐4 inhibitors in cardiovascular and renal protection

Tomovic

Lazarević

Kocić

et al. 2018

Medicinal Research Reviews

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Dipeptidyl peptidase-4 (DPP-4) cleaves N-terminal dipeptides, with Pro, Ala or Ser at the penultimate position, and, in that way, modulates biological activity of certain polypeptides. Due to its ubiquitous distribution, many pathological processes are associated with altered DPP-4 expression and activity. Besides the regulation of glucose metabolism, DPP-4 also exhibits many other systemic effects, and the inhibition of its activity might lead to cardiovascular and renal protection. Mechanisms underlying these protective effects of DPP-4 inhibition are ascribed to elevated bioavailability of its substrates, to impacts on mediators and signaling pathways that ameliorate cardiovascular and renal function through the suppression of oxidative stress, inflammation, fibrosis and apoptosis, improved endothelial function and tissue reparation. Inflammation contributes to and promotes progression of cardiovascular and renal disorders. Herein, we discuss cellular and molecular mechanisms mediating the anti-inflammatory activity of clinically used DPP-4 inhibitors in cardiovascular and renal protection.

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Dipeptidyl peptidase-4 inhibition by gemigliptin prevents abnormal vascular remodeling via NF-E2-related factor 2 activation

Cited by 51 publications

References 43 publications

Hepatoprotective effect of sitagliptin against methotrexate induced liver toxicity

Hepatoprotective effect of sitagliptin against methotrexate induced liver toxicity

Direct effects of DPP-4 inhibition on the vasculature. Reconciling basic evidence with lack of clinical evidence

Mechanisms and pathways of anti‐inflammatory activity of DPP‐4 inhibitors in cardiovascular and renal protection

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