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Dipeptidyl peptidases in atherosclerosis: expression and role in macrophage differentiation, activation and apoptosis

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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.

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Abbreviations

AV:

Annexin V

DPP:

Dipeptidyl peptidase

ECs:

Endothelial cells

GM-CSF:

Granulocyte macrophage-colony stimulating factor

M-CSF:

Macrophage-colony stimulating factor

MDMs:

Monocyte-derived macrophages

Mo:

Monocytes

Mφ:

Macrophages

NPY:

Neuropeptide Y

PI:

Propidium iodide

PBMCs:

Peripheral blood mononuclear cells

PMA:

Phorbol 12-myristate 13-acetate

SMCs:

Smooth muscle cells

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Acknowledgments

This work was supported by the Fund for Scientific Research Flanders (Belgium, FWO-Vlaanderen, Grant no. G016209) and by GOA BOF and TOP BOF (Research Council, Special Fund for Research, University of Antwerp). Veerle Matheeussen and Yannick Waumans are research assistants of FWO-Vlaanderen. We are grateful to Mrs. Rita Van Den Bossche and Mrs. Yani Sim for their excellent technical assistance.

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The authors declare that they have no conflict of interest.

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Matheeussen, V., Waumans, Y., Martinet, W. et al. Dipeptidyl peptidases in atherosclerosis: expression and role in macrophage differentiation, activation and apoptosis. Basic Res Cardiol 108, 350 (2013). https://doi.org/10.1007/s00395-013-0350-4

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