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