Elsevier

Atherosclerosis

Volume 226, Issue 2, February 2013, Pages 305-314
Atherosclerosis

Review
An emerging role of dipeptidyl peptidase 4 (DPP4) beyond glucose control: Potential implications in cardiovascular disease

https://doi.org/10.1016/j.atherosclerosis.2012.09.012Get rights and content

Abstract

The introduction of dipeptidyl peptidase 4 (DPP4) inhibitors for the treatment of Type 2 diabetes acknowledges the fundamental importance of incretin hormones in the regulation of glycemia. Small molecule inhibitors of DPP4 exert their effects via inhibition of enzymatic degradation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). The widespread expression of DPP4 in tissues such as the vasculature and immune cells suggests that this protein may play a role in cardiovascular function. DPP4 is known to exert its effects via both enzymatic and non-enzymatic mechanisms. A soluble form of DPP4 lacking the cytoplasmic and transmembrane domain has also been recently recognized. Besides enzymatic inactivation of incretins, DPP4 also mediates degradation of many chemokines and neuropeptides. The non-enzymatic function of DPP4 plays a critical role in providing co-stimulatory signals to T cells via adenosine deaminase (ADA). DPP4 may also regulate inflammatory responses in innate immune cells such as monocytes and dendritic cells. The multiplicity of functions and targets suggests that DPP4 may play a distinct role aside from its effects on the incretin axis. Indeed recent studies in experimental models of atherosclerosis provide evidence for a robust effect for these drugs in attenuating inflammation and plaque development. Several prospective randomized controlled clinical trials in humans with established atherosclerosis are testing the effects of DPP4 inhibition on hard cardiovascular events.

Introduction

Dipeptidyl peptidase 4 (DPP4, also known as CD26) is widely known for its role in regulation of glycemia through catabolism of incretin peptides. It is now widely recognized that DPP4 subserves many roles. It appears to play an important role in signaling, in cell–matrix interactions and in the regulation of functional activity of many peptides. These activities confer a broad range of functions on DPP4 with implications for a potential pathophysiologic role in both metabolic and inflammatory disorders. In this review the emerging role for DPP4 in cardiometabolic disorders will be discussed.

Section snippets

Biochemistry, tissue distribution of DPP4 and family members

DPP4 is a 766-amino-acid membrane protein that belongs to a family of homologous enzymes that cleave N-terminal dipeptides from proteins containing proline or alanine in the penultimate position [1]. The DPP family consists of several members: DPP4, quiescent cell proline dipeptidase (QPP), fibroblast activation protein (FAP), DPP8, and DPP9 [2] that cleave a diverse range of proteins including glucagon-like peptide (GLP)-1 and 2, glucose-dependent insulinotropic peptide (GIP), neuropeptide Y

Physiologic function of DPP4

The functional role for membrane bound DPP4 relates to both its enzymatic and non-catalytic functions via binding to contiguous proteins on the cell membrane or in the extra-cellular matrix. Depending on the physiologic and pathologic context, both enzymatic and non-catalytic function may be important.

DPP4 mediated signaling pathways

The signaling pathways mediated by DPP4 are not completely understood and what is known varies depending on the cell type, context and the microenvironment (Fig. 2). In this section, we will briefly describe DPP4-mediated signaling as it pertains to immune cell and cardiovascular cells.

Cardiovascular effects of DPP4 inhibition

Since 2006, several DPP4 inhibitors have been approved for the clinical therapy for type 2 diabetes. Recently, there are several lines of evidence suggesting that these drugs may confer cardioprotective effects via both GLP-1 dependent and independent effects.

Conclusion

The development of DPP4 inhibitors and a central role for these agents in glycemic control have brought into focus the importance of DPP4 and its potential role in cardiovascular physiology and pathology. Recent studies indicated that in addition to regulation of post-prandial glycemia, DPP4 may have pleiotropic effects and that its inhibition may have a role in the treatment of inflammatory diseases such as atherosclerosis. A better understanding of the role of DPP4 is will allow its use in

Conflict of interest disclosures

Dr. Rajagopalan was partially supported by RO1 EO015146, R01ES017290, R21 HL108467 and R21 DK088522. Jixin Zhong was supported by RC063384OSU and 81101553/H1604 from NSFC.

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