title: Gliptin and GLP-1 analog treatment improves survival and vascular inflammation/dysfunction in animals with lipopolysaccharide-induced endotoxemia.
abstract: Dipeptidyl peptidase (DPP)-4 inhibitors are used to treat hyperglycemia by increasing the incretin glucagon-like peptide-1 (GLP-1). Previous studies showed anti-inflammatory and antiatherosclerotic effects of DPP-4 inhibitors. Here, we compared the effects of linagliptin versus sitagliptin and liraglutide on survival and vascular function in animal models of endotoxic shock by prophylactic therapy and treatment after lipopolysaccharide (LPS) injection. Gliptins were administered either orally or subcutaneously: linagliptin (5 mg/kg/day), sitagliptin (50 mg/kg/day) or liraglutide (200 µg/kg/day). Endotoxic shock was induced by LPS injection (mice 17.5-20 mg/kg i.p., rats 10 mg/kg/day). Linagliptin and liraglutide treatment or DPP-4 knockout improved the survival of endotoxemic mice, while sitagliptin was ineffective. Linagliptin, liraglutide and sitagliptin ameliorated LPS-induced hypotension and vascular dysfunction in endotoxemic rats, suppressed inflammatory parameters such as whole blood nitrosyl-iron hemoglobin (leukocyte-inducible nitric oxide synthase activity) or aortic mRNA expression of markers of inflammation as well as whole blood and aortic reactive oxygen species formation. Hemostasis (tail bleeding time, activated partial thromboplastin time) was impaired in endotoxemic rats and recovered under cotreatment with linagliptin and liraglutide. Finally, the beneficial effects of linagliptin on vascular function and inflammatory parameters in endotoxemic mice were impaired in AMP-activated kinase (alpha1) knockout mice. The improved survival of endotoxemic animals and other data shown here may warrant further clinical evaluation of these drugs in patients with septic shock beyond the potential improvement of inflammatory complications in diabetic individuals with special emphasis on the role of AMP-activated kinase (alpha1) in the DPP-4/GLP-1 cascade.
authors.affiliation: Department of Cardiology, 2nd Medical Clinic, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Steven
authors.forename: Michael
authors.initials: M
authors.lastname: Hausding
authors.forename: Swenja
authors.initials: S
authors.lastname: Kröller-Schön
authors.forename: Michael
authors.initials: M
authors.lastname: Mader
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Mikhed
authors.forename: Paul
authors.initials: P
authors.lastname: Stamm
authors.forename: Elena
authors.initials: E
authors.lastname: Zinßius
authors.forename: Amanda
authors.initials: A
authors.lastname: Pfeffer
authors.forename: Philipp
authors.initials: P
authors.lastname: Welschof
authors.forename: Saule
authors.initials: S
authors.lastname: Agdauletova
authors.forename: Stephan
authors.initials: S
authors.lastname: Sudowe
authors.forename: Huige
authors.initials: H
authors.lastname: Li
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schulz
authors.forename: Thomas
authors.initials: T
authors.lastname: Klein
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
mesh_terms: D000818:Animals; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000503:physiopathology*; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D007249:Inflammation / Q000503:physiopathology; D000069476:Linagliptin; D008070:Lipopolysaccharides / Q000633:toxicity; D000069450:Liraglutide; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D011687:Purines / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D008070:Lipopolysaccharides; D011687:Purines; D011719:Pyrazines; D011799:Quinazolines; D014230:Triazoles; D000069476:Linagliptin; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D000068900:Sitagliptin Phosphate