title: Glucose-independent improvement of vascular dysfunction in experimental sepsis by dipeptidyl-peptidase 4 inhibition.
abstract: OBJECTIVE
  Dipeptidyl peptidase-4 (DPP-4) inhibitors are a novel class of drugs for the treatment of hyperglycaemia. Preliminary evidence suggests that their antioxidant and anti-inflammatory effects may have beneficial effects on the cardiovascular complications of diabetes. In the present study, we investigate in an experimental sepsis model whether linagliptin exerts pleiotropic vascular effects independent of its glucose-lowering properties.
  
  
  RESULTS
  Linagliptin (83 mg/kg chow for 7 days) was administered in a rat model of lipopolysaccharide (LPS) (10 mg/kg, single i.p. dose/24 h)-induced sepsis. Vascular relaxation, reactive oxygen species (ROS) formation, expression of NADPH oxidase subunits and proinflammatory markers, and white blood cell infiltration in the vasculature were determined. Oxidative burst and adhesion of isolated human neutrophils to endothelial cells were measured in the presence of different DPP-4 inhibitors, and their direct vasodilatory effects (isometric tension in isolated aortic rings) were compared. In vivo linagliptin treatment ameliorated LPS-induced endothelial dysfunction and was associated with reduced formation of vascular, cardiac, and blood ROS, aortic expression of inflammatory genes and NADPH oxidase subunits in addition to reduced aortic infiltration with inflammatory cells. Linagliptin was the most potent inhibitor of oxidative burst in isolated activated human neutrophils and it suppressed their adhesion to activated endothelial cells. Of the inhibitors tested, linagliptin and alogliptin had the most pronounced direct vasodilatory potency.
  
  
  CONCLUSIONS
  Linagliptin demonstrated pleiotropic vasodilatory, antioxidant, and anti-inflammatory properties independent of its glucose-lowering properties. These pleiotropic properties are generally not shared by other DPP-4 inhibitors and might translate into cardiovascular benefits in diabetic patients.
authors: Department of Cardiology,  2nd Medical Clinic, Medical Center of the Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz,  Germany.
authors: Swenja
authors: S
authors: Kröller-Schön
authors: Maike
authors: M
authors: Knorr
authors: Michael
authors: M
authors: Hausding
authors: Matthias
authors: M
authors: Oelze
authors: Alexandra
authors: A
authors: Schuff
authors: Richard
authors: R
authors: Schell
authors: Stephan
authors: S
authors: Sudowe
authors: Alexander
authors: A
authors: Scholz
authors: Steffen
authors: S
authors: Daub
authors: Susanne
authors: S
authors: Karbach
authors: Sabine
authors: S
authors: Kossmann
authors: Tommaso
authors: T
authors: Gori
authors: Philip
authors: P
authors: Wenzel
authors: Eberhard
authors: E
authors: Schulz
authors: Stephan
authors: S
authors: Grabbe
authors: Thomas
authors: T
authors: Klein
authors: Thomas
authors: T
authors: Münzel
authors: Andreas
authors: A
authors: Daiber
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000032:analysis; D003925:Diabetic Angiopathies / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007962:Leukocytes / Q000187:drug effects; D000069476:Linagliptin; D008070:Lipopolysaccharides; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D011687:Purines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D016897:Respiratory Burst / Q000187:drug effects; D018805:Sepsis / Q000188:drug therapy*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D054873:Dipeptidyl-Peptidase IV Inhibitors; D008070:Lipopolysaccharides; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin