title: Soluble dipeptidyl peptidase-4 induces microvascular endothelial dysfunction through proteinase-activated receptor-2 and thromboxane A2 release.
abstract: BACKGROUND
  Dipeptidyl peptidase-4 (DPP4) is a key protein in glucose homeostasis and a pharmacological target in type 2 diabetes mellitus. This study explored whether the novel adipokine soluble DPP4 (sDPP4) can cause endothelial dysfunction, an early marker of impaired vascular reactivity.
  
  
  METHODS
  Reactivity was studied in mesenteric arteries from 3-month-old female mice, using a small vessel myograph. Thromboxane A2 (TXA2) release was explored in cultured human coronary artery endothelial cells by enzyme immunoassay.
  
  
  RESULTS
  Neither the contractility to noradrenaline nor the endothelium-independent relaxations induced by sodium nitroprusside were modified by sDPP4. However, sDPP4 impaired in a concentration-dependent manner the endothelium-dependent relaxation elicited by acetylcholine. The DPP4 inhibitors K579 and linagliptin prevented the defective relaxation induced by sDPP4, as did the protease-activated receptor 2 (PAR2) inhibitor GB83. Downstream of PAR2, the cyclooxygenase (COX) inhibitor indomethacin, the COX2 inhibitor celecoxib or the thromboxane receptors blocker SQ29548 prevented the deleterious effects of sDPP4. Accordingly, sDPP4 triggered the release of TXA2 by endothelial cells, whereas TXA2 release was prevented by inhibiting DPP4, PAR2 or COX.
  
  
  CONCLUSIONS
  In summary, these findings reveal sDPP4 as a direct mediator of endothelial dysfunction, acting through PAR2 activation and the release of vasoconstrictor prostanoids. By interfering with these actions, DPP4 inhibitors might help preserving endothelial function in the context of cardiometabolic diseases.
authors.affiliation: aPaul Langerhans Group for Integrative Physiology, German Diabetes Center, Düsseldorf, Germany bDepartment of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain cGerman Center for Diabetes Research (DZD e.V.), Düsseldorf, Germany *Carlos F. Sánchez-Ferrer and Concepción Peiró jointly directed this work.
authors.forename: Tania
authors.initials: T
authors.lastname: Romacho
authors.forename: Susana
authors.initials: S
authors.lastname: Vallejo
authors.forename: Laura A
authors.initials: LA
authors.lastname: Villalobos
authors.forename: Nina
authors.initials: N
authors.lastname: Wronkowitz
authors.forename: Ira
authors.initials: I
authors.lastname: Indrakusuma
authors.forename: Henrike
authors.initials: H
authors.lastname: Sell
authors.forename: Jüergen
authors.initials: J
authors.lastname: Eckel
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Sánchez-Ferrer
authors.forename: Concepción
authors.initials: C
authors.lastname: Peiró
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4 / Q000009:adverse effects / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D008638:Mesenteric Arteries / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D044464:Receptor, PAR-2 / Q000378:metabolism*; D013928:Thromboxane A2 / Q000378:metabolism*
chemical_list: D044464:Receptor, PAR-2; D013928:Thromboxane A2; D018819:Dipeptidyl Peptidase 4