Suppression of abdominal aortic aneurysm formation in mice by teneligliptin, a dipeptidyl peptidase-4 inhibitor

Yusuke Takahara, Tomotake Tokunou, Toshihiro Ichiki

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Aim: Dipeptidyl peptidase-4 (DPP-4) inhibitors lower blood glucose levels through inhibition of incretin degradation, which stimulates insulin secretion. Recent studies reported that DPP-4 inhibitors suppressed atherogenesis in apolipoprotein E-knockout (ApoEKO) mice. In this study, we investigated whether teneligliptin, a DPP-4 inhibitor, affects the development of abdominal aortic aneurysms (AAA) in ApoEKO mice. Methods: ApoEKO mice were fed a high-fat diet (HFD) and infused with angiotensin (Ang) Ⅱ by osmotic mini pumps for 4 weeks to induce AAA with (DPP-4i group) or without (control group) teneligliptin administered orally from 1 week before HFD and Ang Ⅱ infusion to the end of the experiment. Confluent rat vascular smooth muscle cells (VSMCs) were serum-starved for 48 hours, then incubated with or without teneligliptin for another 24 hours and stimulated with Ang Ⅱ. Results: Treatment with teneligliptin significantly reduced the AAA formation rate (30.7% vs. 71.4% vs. control, P <0.05), aortic dilatation (1.32±0.09 mm vs. 1.76±0.18 mm in the control, P <0.05) and severity score (0.75±0.28 vs. 1.91±0.4 in the control, P <0.05). Elastin degradation grade was also attenuated in DPP-4i group (2.83±0.17 vs. 3.45±0.16 in the control, P <0.05). The number of macrophages infiltrating into the abdominal aorta was decreased in the DPP-4i group (51.8±29.8/section vs. 219.5±78.5/section in the control, P <0.05). Teneligliptin attenuated Ang Ⅱ-induced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, and mRNA expression of monocyte chemoattractant protein-1 in VSMCs. Conclusion: Treatment with teneligliptin suppressed AAA formation in ApoEKO mice with HFD and Ang Ⅱ infusion. Suppression of macrophage infiltration by teneligliptin may be involved in the inhibition of AAA formation.

Original languageEnglish
Pages (from-to)698-708
Number of pages11
JournalJournal of atherosclerosis and thrombosis
Volume25
Issue number8
DOIs
Publication statusPublished - Jan 1 2018

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Dipeptidyl-Peptidase IV Inhibitors
Abdominal Aortic Aneurysm
Angiotensins
Apolipoproteins E
Knockout Mice
High Fat Diet
Nutrition
Macrophages
Fats
Vascular Smooth Muscle
Smooth Muscle Myocytes
Muscle
Incretins
Degradation
Phosphorylation
Elastin
Chemokine CCL2
Abdominal Aorta
Extracellular Signal-Regulated MAP Kinases
3-(4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl)thiazolidine

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Cardiology and Cardiovascular Medicine
  • Biochemistry, medical

Cite this

Suppression of abdominal aortic aneurysm formation in mice by teneligliptin, a dipeptidyl peptidase-4 inhibitor. / Takahara, Yusuke; Tokunou, Tomotake; Ichiki, Toshihiro.

In: Journal of atherosclerosis and thrombosis, Vol. 25, No. 8, 01.01.2018, p. 698-708.

Research output: Contribution to journalArticle

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abstract = "Aim: Dipeptidyl peptidase-4 (DPP-4) inhibitors lower blood glucose levels through inhibition of incretin degradation, which stimulates insulin secretion. Recent studies reported that DPP-4 inhibitors suppressed atherogenesis in apolipoprotein E-knockout (ApoEKO) mice. In this study, we investigated whether teneligliptin, a DPP-4 inhibitor, affects the development of abdominal aortic aneurysms (AAA) in ApoEKO mice. Methods: ApoEKO mice were fed a high-fat diet (HFD) and infused with angiotensin (Ang) Ⅱ by osmotic mini pumps for 4 weeks to induce AAA with (DPP-4i group) or without (control group) teneligliptin administered orally from 1 week before HFD and Ang Ⅱ infusion to the end of the experiment. Confluent rat vascular smooth muscle cells (VSMCs) were serum-starved for 48 hours, then incubated with or without teneligliptin for another 24 hours and stimulated with Ang Ⅱ. Results: Treatment with teneligliptin significantly reduced the AAA formation rate (30.7{\%} vs. 71.4{\%} vs. control, P <0.05), aortic dilatation (1.32±0.09 mm vs. 1.76±0.18 mm in the control, P <0.05) and severity score (0.75±0.28 vs. 1.91±0.4 in the control, P <0.05). Elastin degradation grade was also attenuated in DPP-4i group (2.83±0.17 vs. 3.45±0.16 in the control, P <0.05). The number of macrophages infiltrating into the abdominal aorta was decreased in the DPP-4i group (51.8±29.8/section vs. 219.5±78.5/section in the control, P <0.05). Teneligliptin attenuated Ang Ⅱ-induced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, and mRNA expression of monocyte chemoattractant protein-1 in VSMCs. Conclusion: Treatment with teneligliptin suppressed AAA formation in ApoEKO mice with HFD and Ang Ⅱ infusion. Suppression of macrophage infiltration by teneligliptin may be involved in the inhibition of AAA formation.",
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T1 - Suppression of abdominal aortic aneurysm formation in mice by teneligliptin, a dipeptidyl peptidase-4 inhibitor

AU - Takahara, Yusuke

AU - Tokunou, Tomotake

AU - Ichiki, Toshihiro

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Aim: Dipeptidyl peptidase-4 (DPP-4) inhibitors lower blood glucose levels through inhibition of incretin degradation, which stimulates insulin secretion. Recent studies reported that DPP-4 inhibitors suppressed atherogenesis in apolipoprotein E-knockout (ApoEKO) mice. In this study, we investigated whether teneligliptin, a DPP-4 inhibitor, affects the development of abdominal aortic aneurysms (AAA) in ApoEKO mice. Methods: ApoEKO mice were fed a high-fat diet (HFD) and infused with angiotensin (Ang) Ⅱ by osmotic mini pumps for 4 weeks to induce AAA with (DPP-4i group) or without (control group) teneligliptin administered orally from 1 week before HFD and Ang Ⅱ infusion to the end of the experiment. Confluent rat vascular smooth muscle cells (VSMCs) were serum-starved for 48 hours, then incubated with or without teneligliptin for another 24 hours and stimulated with Ang Ⅱ. Results: Treatment with teneligliptin significantly reduced the AAA formation rate (30.7% vs. 71.4% vs. control, P <0.05), aortic dilatation (1.32±0.09 mm vs. 1.76±0.18 mm in the control, P <0.05) and severity score (0.75±0.28 vs. 1.91±0.4 in the control, P <0.05). Elastin degradation grade was also attenuated in DPP-4i group (2.83±0.17 vs. 3.45±0.16 in the control, P <0.05). The number of macrophages infiltrating into the abdominal aorta was decreased in the DPP-4i group (51.8±29.8/section vs. 219.5±78.5/section in the control, P <0.05). Teneligliptin attenuated Ang Ⅱ-induced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, and mRNA expression of monocyte chemoattractant protein-1 in VSMCs. Conclusion: Treatment with teneligliptin suppressed AAA formation in ApoEKO mice with HFD and Ang Ⅱ infusion. Suppression of macrophage infiltration by teneligliptin may be involved in the inhibition of AAA formation.

AB - Aim: Dipeptidyl peptidase-4 (DPP-4) inhibitors lower blood glucose levels through inhibition of incretin degradation, which stimulates insulin secretion. Recent studies reported that DPP-4 inhibitors suppressed atherogenesis in apolipoprotein E-knockout (ApoEKO) mice. In this study, we investigated whether teneligliptin, a DPP-4 inhibitor, affects the development of abdominal aortic aneurysms (AAA) in ApoEKO mice. Methods: ApoEKO mice were fed a high-fat diet (HFD) and infused with angiotensin (Ang) Ⅱ by osmotic mini pumps for 4 weeks to induce AAA with (DPP-4i group) or without (control group) teneligliptin administered orally from 1 week before HFD and Ang Ⅱ infusion to the end of the experiment. Confluent rat vascular smooth muscle cells (VSMCs) were serum-starved for 48 hours, then incubated with or without teneligliptin for another 24 hours and stimulated with Ang Ⅱ. Results: Treatment with teneligliptin significantly reduced the AAA formation rate (30.7% vs. 71.4% vs. control, P <0.05), aortic dilatation (1.32±0.09 mm vs. 1.76±0.18 mm in the control, P <0.05) and severity score (0.75±0.28 vs. 1.91±0.4 in the control, P <0.05). Elastin degradation grade was also attenuated in DPP-4i group (2.83±0.17 vs. 3.45±0.16 in the control, P <0.05). The number of macrophages infiltrating into the abdominal aorta was decreased in the DPP-4i group (51.8±29.8/section vs. 219.5±78.5/section in the control, P <0.05). Teneligliptin attenuated Ang Ⅱ-induced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, and mRNA expression of monocyte chemoattractant protein-1 in VSMCs. Conclusion: Treatment with teneligliptin suppressed AAA formation in ApoEKO mice with HFD and Ang Ⅱ infusion. Suppression of macrophage infiltration by teneligliptin may be involved in the inhibition of AAA formation.

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