Abstract 15482: Effects of DPP4-inhibition on Endothelial Function and Hemostasis in a Rodent Model of Septic Shock
Introduction: Sepsis is an inflammatory state. Proinflammatory enzymes like inducible-NO Synthase (iNOS) and NADPH-Oxidase (NOX) are activated and influence endothelial function via oxidative and nitrosative stress. Inhibition of dipeptidyl-peptidase 4 (DPP4i) is a new approach to treat diabetic patients. Matubara et al. (Circulation, 2012) showed a positive influence of DPP4i on endothelial function in an animal model
Hypothesis: DPP4 inhibition influences endothelial function, hemostasis and survival in a rodent model of septic shock
Methods: C57/BL6j mice were pretreated with different DPP4i (linagliptin, sitagliptin) and GLP-1-analogue (GLP1a) liraglutide for 3 days. Aorta and heart tissue was used for western-blotting and rtPCR. Blood was examined for coagulation parameters (aPTT, PT), cell count and oxidative stress
Results: Treatment with DPP4i and GLP1-a improved survival and blood pressure of septic animals significantly. LPS-induced oxidative stress and nitrosylated hemoglobin (Hb-NO) levels were reduced by DPP4i and GLP1a. In accordance to this observation iNOS-expression was down regulated by DPP4i. Nitration of prostacyclin synthase (PGIS) was increased in septic animals and normalized by DPP4i. Endothelium-dependent relaxation was impaired in LPS-treated animals and improved by DPP4i and GLP1a. Inflammatory parameters (i.e. IL6) which were up regulated by LPS could be decreased by DPP4i. In addition, DPP4i had beneficial effects on coagulation parameters like aPTT, PT und platelet-count
Conclusions: Oxidative stress plays a major role in sepsis. Activation of iNOS and NOX is a cellular response in LPS-induced sepsis. This causes high levels of NO and superoxide reacting to peroxynitrite (ONOO-). We here confirm previous results that nitration of PGIS causes vascular dysfunction in sepsis. DPP4i reduces iNOS expression and superoxide generation. All of which ameliorates nitration of PGIS, improves vascular and platelet function. As a direct consequence disseminated intravasal coagulation (DIC) was avoided. Therefore, the improvement of vascular function by reduction of oxidative stress and a normalization of the thrombotic/hemostatic balance may contribute to an increased survival of septic animals by DPP4i
Author Disclosures: S. Steven: None. M. Hausding: None. S. Kröller-Schön: None. Y. Mikhed: None. M. Oelze: None. T. Münzel: None. A. Daiber: None.
- © 2014 by American Heart Association, Inc.