Hotimah Masdan Salim1, Daiju Fukuda2, Yasutomi Higashikuni3, Kimie Tanaka4, Yoichiro Hirata5, Shusuke Yagi1, Takeshi Soeki1, Michio Shimabukuro6, Masataka Sata1. 1. Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan. 2. Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan. Electronic address: daiju.fukuda@tokushima-u.ac.jp. 3. Department of Cardiovascular Medicine, The University of Tokyo, Japan. 4. Division for Health Service Promotion, The University of Tokyo, Japan. 5. Department of Pediatrics, The University of Tokyo Hospital, Japan. 6. Department of Cardio-Diabetes Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan.
Abstract
BACKGROUND: 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 (10mg/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.
BACKGROUND: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-diabeticapolipoprotein-E deficient (ApoE(-/-)) mice, and examined its effects on endothelial function. METHODS AND RESULTS:Lina (10mg/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-diabeticApoE(-/-) mice. Amelioration of endothelial dysfunction associated with a reduction of oxidative stress by GLP-1 contributes to the atheroprotective effects of Lina.
Authors: Camila Manrique; Javad Habibi; Annayya R Aroor; James R Sowers; Guanghong Jia; Melvin R Hayden; Mona Garro; Luis A Martinez-Lemus; Francisco I Ramirez-Perez; Thomas Klein; Gerald A Meininger; Vincent G DeMarco Journal: Cardiovasc Diabetol Date: 2016-07-08 Impact factor: 9.951
Authors: Thomas Jax; Alin Stirban; Arne Terjung; Habib Esmaeili; Andreas Berk; Sandra Thiemann; Robert Chilton; Maximilian von Eynatten; Nikolaus Marx Journal: Cardiovasc Diabetol Date: 2017-01-21 Impact factor: 9.951