title: Loss of DPP4 activity is related to a prothrombogenic status of endothelial cells: implications for the coronary microvasculature of myocardial infarction patients.
abstract: Pro-coagulant and pro-inflammatory intramyocardial (micro)vasculature plays an important role in acute myocardial infarction (AMI). Currently, inhibition of serine protease dipeptidyl peptidase 4 (DPP4) receives a lot of interest as an anti-hyperglycemic therapy in type 2 diabetes patients. However, DPP4 also possesses anti-thrombotic properties and may behave as an immobilized anti-coagulant on endothelial cells. Here, we studied the expression and activity of endothelial DPP4 in human myocardial infarction in relation to a prothrombogenic endothelial phenotype. Using (immuno)histochemistry, DPP4 expression and activity were found on the endothelium of intramyocardial blood vessels in autopsied control hearts (n = 9). Within the infarction area of AMI patients (n = 73), this DPP4 expression and activity were significantly decreased, coinciding with an increase in Tissue Factor expression. In primary human umbilical vein endothelial cells (HUVECs), Western blot analysis and digital imaging fluorescence microscopy revealed that DPP4 expression was strongly decreased after metabolic inhibition, also coinciding with Tissue Factor upregulation. Interestingly, inhibition of DPP4 activity with diprotin A also enhanced the amount of Tissue Factor encountered and induced the adherence of platelets under flow conditions. Ischemia induces loss of coronary microvascular endothelial DPP4 expression and increased Tissue Factor expression in AMI as well as in vitro in HUVECs. Our data suggest that the loss of DPP4 activity affects the anti-thrombogenic nature of the endothelium.
authors.affiliation: Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1007 MB, Amsterdam, The Netherlands. paj.krijnen@vumc.nl
authors.forename: Paul A J
authors.initials: PA
authors.lastname: Krijnen
authors.forename: Nynke E
authors.initials: NE
authors.lastname: Hahn
authors.forename: Ivana
authors.initials: I
authors.lastname: Kholová
authors.forename: Umit
authors.initials: U
authors.lastname: Baylan
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Sipkens
authors.forename: Floris P
authors.initials: FP
authors.lastname: van Alphen
authors.forename: Alexander B A
authors.initials: AB
authors.lastname: Vonk
authors.forename: Suat
authors.initials: S
authors.lastname: Simsek
authors.forename: Christof
authors.initials: C
authors.lastname: Meischl
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
authors.forename: Jaap D
authors.initials: JD
authors.lastname: van Buul
authors.forename: Victor W M
authors.initials: VW
authors.lastname: van Hinsbergh
authors.forename: Hans W M
authors.initials: HW
authors.lastname: Niessen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003328:Coronary Thrombosis / Q000201:enzymology*; D003331:Coronary Vessels / Q000201:enzymology*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology; D006801:Humans; D008297:Male; D055806:Microvessels / Q000201:enzymology*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000201:enzymology*; D009206:Myocardium / Q000201:enzymology; D010973:Platelet Adhesiveness; D013925:Thromboplastin / Q000378:metabolism
chemical_list: D013925:Thromboplastin; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4