Dipeptidyl peptidase-4 inhibitor, linagliptin, ameliorates endothelial dysfunction and atherogenesis in normoglycemic apolipoprotein-E deficient mice

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• 作者：Hotimah Masdan Salim^a ; Daiju Fukuda^a ; ^{daiju.fukuda@tokushima-u.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Yasutomi Higashikuni^b ; Kimie Tanaka^c ; Yoichiro Hirata^d ; Shusuke Yagi^a ; Takeshi Soeki^a ; Michio Shimabukuro^e ; Masataka Sata^a
• 关键词：DPP-4 ; dipeptidyl peptidase-4 ; Lina ; linagliptin ; ApoE&minus ; /&minus ; apolipoprotein-E deficient ; GLP-1 ; glucagon-like peptide-1 ; Ex-4 ; exendin-4 ; PA ; palmitic acid ; WTD ; western-type diet ; CMC ; carboxymethyl cellulose ; 8-OHdG ; 8-hydroxy-2&prime ; -deoxyguanosine ; MCP-1 ; monocyte chemoattractant protein-1 ; VCAM-1 ; vascular cellular adhesion molecule-1 ; Mac-3 ; macrophage antigen-3 ; Ach ; acetylcholine ; SNP ; sodium nitroprusside ; HUVEC ; human umbilical vein endothelial cell ; VEGF ; vascular endotheli
• 刊名：Vascular Pharmacology
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：79
• 期：Complete
• 页码：16-23
• 全文大小：1126 K

文摘

Dipeptidyl peptidase-4 (DPP-4) inhibitors have vasoprotective effects. This study investigated whether a recently approved DPP-4 inhibitor, linagliptin (Lina), suppresses atherogenesis in non-diabetic apolipoprotein-E deficient (ApoE^−/−) mice, and examined its effects on endothelial function.

Methods and results

Lina (10 mg/kg/day) was administered orally to ApoE^−/− mice for 20 weeks. Lina reduced atherogenesis without alteration of metabolic parameters including blood glucose level compared with control (P < 0.05). Results of immunohistochemical analyses and quantitative RT-PCR demonstrated that Lina significantly decreased inflammatory molecule expression and macrophage infiltration in the atherosclerotic aorta. Lina administration to ApoE^−/− mice for 9 weeks ameliorated endothelium-dependent vasodilation compared with that in untreated mice. Plasma active glucagon-like peptide-1 (GLP-1) level was significantly higher in the treated group (P < 0.05). Exendin-4 (Ex-4), a GLP-1 analog, ameliorated endothelium-dependent vasodilation impaired by palmitic acid (PA) in wild-type mouse aortic segments. Ex-4 promoted phosphorylation of eNOS^Ser1177 and Akt, both of which were abrogated by PA, in human umbilical vein endothelial cells. In addition, Lina administration to ApoE^−/− mice decreased oxidative stress, as determined by urinary 8-OHdG secretion and NADPH oxidase subunit expression in the abdominal aorta.

Conclusion

Lina inhibited atherogenesis in non-diabetic ApoE^−/− mice. Amelioration of endothelial dysfunction associated with a reduction of oxidative stress by GLP-1 contributes to the atheroprotective effects of Lina.