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.

Gliptin and GLP‐1 analog treatment improves survival and vascular inflammation/dysfunction in animals with lipopolysaccharide‐induced endotoxemia

“…Accordingly, bleeding time and aPTT, reflecting the contact activation pathway of the coagulation system, were substantially impaired in endotoxemic animals and greatly improved by linagliptin and liraglutide all of which may also account for the observed decrease in mortality. Of note, previous studies have attributed antithrombotic activity of DPP-4 on endothelial cells by decreasing tissue factor in acute myocardial infarction, which is at variance with our present observations [20].…”

Sitagliptin induced splenic infarcts

“…DPP-4 has the potential to inhibit fibrin polymerization and clot formation [8,9]. Thus DPP-4 may behave as an immobilized anti-coagulant on microvascular endothelium and possesses antithrombotic properties; decreased DPP-4 expression and activity has been found to coincide with an increase in Tissue Factor expression and induction of in situ thrombosis [10]. Inhibition of DPP-4 activity also induces adhesion of platelets; this may be another mechanism of thrombosis which occurs with inhibition of DPP-4 activity [10].…”

Heart Failure as a Comorbidity of Diabetes: Role of Dipeptidyl Peptidase 4

“…DPP4 per se possesses anti-thrombotic properties and may behave as an immobilized anti-coagulant on endothelial cells. Under nondiabetic conditions, ischemia/ hypoxia induces the loss of coronary microvascular endothelial DPP4 expression and increased tissue factor expression in AMI 56) .…”