title: Dipeptidyl peptidases in atherosclerosis: expression and role in macrophage differentiation, activation and apoptosis.
abstract: Atherosclerosis is a chronic inflammatory disorder of the arterial wall leading to coronary artery disease, stroke, and peripheral arterial disease. Along with the discovery of dipeptidyl peptidase 4 (DPP4) as a therapeutic target in type 2 diabetes, a role for DPP4 in atherosclerosis is emerging. However, until now the expression and role of other DPPs such as DPP8 and DPP9 in atherosclerosis is completely unknown. In the present study, we first investigated DPP expression in human atherosclerotic plaques. DPP4 could only be observed in endothelial cells of plaque neovessels in half of the specimens. In contrast, DPP8 and DPP9 were abundantly present in macrophage-rich regions of plaques. We then focused on DPP expression and function in macrophage differentiation, activation and apoptosis. DPP8/9 was responsible for most of the DPP activity in macrophages. During monocyte to macrophage differentiation, DPP9 was upregulated both in pro-inflammatory M1 (3.7 ± 0.3-fold increase) and anti-inflammatory M2 macrophages (3.7 ± 0.4-fold increase) whereas DPP8 expression remained unchanged. Inhibition of DPP8/9 activity with compound 1G244 reduced activation of M1 macrophages (IL-6 88 ± 16 vs. 146 ± 19 pg/ml; TNFα 3.8 ± 1.0 vs. 6.6 ± 1.9 ng/ml in treated vs. untreated cells), but not of M2 macrophages. Likewise, DPP9 silencing reduced TNFα and IL-6 secretion, pointing to a DPP9-mediated effect of the inhibitor. DPP8/9 inhibition also enhanced macrophage apoptosis (15 ± 4 vs. 7 ± 3 % in untreated cells). Because pro-inflammatory macrophages play a key role in atherogenesis, plaque rupture and subsequent infarction, DPP9 inhibition might provide interesting therapeutic prospects in reducing atherosclerosis and/or in the prevention of plaque rupture.
authors.affiliation: Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Veerle
authors.initials: V
authors.lastname: Matheeussen
authors.forename: Yannick
authors.initials: Y
authors.lastname: Waumans
authors.forename: Wim
authors.initials: W
authors.lastname: Martinet
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Van Goethem
authors.forename: Pieter
authors.initials: P
authors.lastname: Van der Veken
authors.forename: Simon
authors.initials: S
authors.lastname: Scharpé
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
authors.forename: Guido R Y
authors.initials: GR
authors.lastname: De Meyer
authors.forename: Ingrid
authors.initials: I
authors.lastname: De Meester
mesh_terms: D017209:Apoptosis; D002339:Carotid Arteries / Q000201:enzymology* / Q000276:immunology / Q000473:pathology / Q000601:surgery; D016893:Carotid Stenosis / Q000201:enzymology* / Q000276:immunology / Q000473:pathology / Q000601:surgery; D002454:Cell Differentiation / Q000187:drug effects; D004150:Dipeptidases / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016894:Endarterectomy, Carotid; D006801:Humans; D007249:Inflammation / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020298:U937 Cells
chemical_list: C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D011480:Protease Inhibitors; D014409:Tumor Necrosis Factor-alpha; D004150:Dipeptidases; C471241:DPP9 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C042807:DPP4 protein, human; C487997:DPP8 protein, human; D018819:Dipeptidyl Peptidase 4