Expression and spatial heterogeneity of dipeptidyl peptidases in endothelial cells of conduct vessels and capillaries

Abstract

Dipeptidyl peptidase IV (DPPIV)/CD26 is by far the most extensively studied member of the prolyl oligopeptidase family of serine proteases. The discovery of the related enzymes DPP8 and DPP9 necessitates a (re-)evaluation of the DPPIV-like enzymatic activity in cells and organs. In this study, we aimed (1) to investigate the expression of the individual dipeptidyl peptidases in different types of endothelial cells (ECs) and (2) to reconsider published data in relation to our findings. Examination of DPP expression in rat primary ECs of aortic, endocardial and cardiac microvascular origin revealed the presence of DPPIV-like activity in all cell lysates. More than half of this activity could be attributed to DPP8/9. Western blot analysis revealed an abundance of the DPP8 protein as compared to DPP9. The expression of DPPIV and DPP8 was significantly higher in the cardiac microvascular endothelium than in the other ECs, suggesting a more pronounced role of these DPPs in the microvasculature. In situ, DPP activity in ventricular microvasculature was completely inhibited by sitagliptin, indicating that DPPIV is the predominant DPPIV-like enzyme in this organ. By contrast, immunohistochemical studies indicated DPP9 as the predominant DPP in human carotid artery ECs. In conclusion, our results support a highly regulated expression of individual DPPs in ECs, with a spatial heterogeneity in the cardiovascular tree.

Advances in Understanding the Expression and Function of Dipeptidyl Peptidase 8 and 9

“…In addition, DPP8 and DPP9 activity is approximately 10-fold lower than DPPIV activity in nonrenal rat and monkey tissues (64). DPPIV and DPP8 are more abundant than DPP9 protein in rat primary endothelial cells, however, about 60% of the total DPP enzyme activity is derived from DPP8/9 rather than DPPIV in these cells (65). DPP9 is the only DPPIV-like enzyme detectable by immunohistochemistry in human carotid artery endothelial cells, whereas DPPIV is the predominant DPPIV-like enzyme in ventricular microvasculature by in situ hybridization (65).…”

Cardiovascular Actions of Incretin-Based Therapies

“…85 Within the heart, DPP-4 has been localized predominantly to endothelial cells. 86,87 DPP-4 exists in 2 molecular forms that display proteolytic activity: a membrane-spanning protein with a short intracellular tail and a circulating protein bereft of the intracellular and membrane-spanning regions. The biology of DPP-4 is complex, with both the membranespanning protein and the soluble circulating form exerting biological activities independent of the catalytic activity of the enzyme.…”

Inhibition of Circulating Dipeptidyl Peptidase 4 Activity in Patients with Metastatic Prostate Cancer

“…Although DPP4 is expressed on numerous cell types, including kidney, liver epithelial cells, and endothelial cells of ventricular microvasculature (34,38,40), T cells are believed to provide the majority of its circulating form (also know as soluble CD26) by partially shedding surface CD26 into the blood stream following proteolytic cleavage (38,41,42). Known DPP4 substrates include growth factors, chemokines, and peptide hormones such as glucagon-like peptide 1, which helps control blood sugar levels (38,(43)(44)(45).…”