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


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.


CONCLUSIONS
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.
Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan.
Hotimah Masdan
HM
Salim
Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan. Electronic address: daiju.fukuda@tokushima-u.ac.jp.
Daiju
D
Fukuda
Department of Cardiovascular Medicine, The University of Tokyo, Japan.
Yasutomi
Y
Higashikuni
Division for Health Service Promotion, The University of Tokyo, Japan.
Kimie
K
Tanaka
Department of Pediatrics, The University of Tokyo Hospital, Japan.
Yoichiro
Y
Hirata
Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan.
Shusuke
S
Yagi
Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan.
Takeshi
T
Soeki
Department of Cardio-Diabetes Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan.
Michio
M
Shimabukuro
Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan.
Masataka
M
Sata
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy*; D001786:Blood Glucose / Q000187:drug effects* / Q000502:physiology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D000069476:Linagliptin / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D001057:Apolipoproteins E; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000069476:Linagliptin; D000109:Acetylcholine
DPP-4 inhibitor; Endothelial function; GLP-1; Inflammation; Linagliptin; Oxidative stress