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

• Published in: Atherosclerosis Vol. 226; no. 2; pp. 305 - 314
• Main Authors: Zhong, Jixin, Rao, Xiaoquan, Rajagopalan, Sanjay
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ireland Ltd 01-02-2013; Elsevier
• Subjects: adenosine deaminase; Animals; Atherosclerosis; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; blood glucose; Blood Pressure - drug effects; Cardiology. Vascular system; Cardiovascular; Cardiovascular Diseases - drug therapy; Cardiovascular Diseases - prevention & control; Cardiovascular System - drug effects; CD26; chemokines; dendritic cells; Diabetes Mellitus, Type 2 - drug therapy; Dipeptidyl Peptidase 4 - physiology; Dipeptidyl Peptidase 4 - therapeutic use; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; DPP4; drugs; enzyme inhibition; Gastric Inhibitory Polypeptide - metabolism; glucagon-like peptide 1; Glucagon-Like Peptide 1 - metabolism; glycemic control; Humans; Incretins - metabolism; Inflammation; Inflammation - drug therapy; Medical sciences; Mice; monocytes; Neuropharmacology; noninsulin-dependent diabetes mellitus; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; randomized clinical trials; secretin; T-lymphocytes; Type 2 diabetes; Type 2 diabetes; monokine induced by IFN-γ; eNOS; chemokine (C-C motif) ligand; BNP; RANTES; neuropeptide Y; endothelial progenitor cell; vasodilator-stimulated phosphoprotein; fibroblast activation protein; MDC; inflammatory protein-10; QPP; T-cell receptor; IFN-γ; monocyte chemotactic protein-1; endothelial nitric oxide synthase; HOMA-β; Rac1; stromal cell-derived factor-1; nitric oxide; antibody; antigen-presenting cells; IL; IP10; NFκB; dipeptidase 4; NOD mouse; PKA; Mig; GIP; ITAC; Ras-related C3 botulinum toxin substrate 1; lipopolysaccharide; MAP; non-obese diabetic mouse; quiescent cell proline dipeptidase; Ab; NO; interferon-γ; mitogen activated protein; MCP-1; TCR; GRP; low-density lipoprotein receptor; zeta-chain-associated protein kinase-70; glucagon-like peptide-1; macrophage derived chemokine; interferon-inducible T cell chemo-attractant; SDF-1; LPS; DPP4; ZAP-70; NF-kappa B; regulated upon activation normal T cell expressed and presumably secreted; NPY; Atherosclerosis; gastrin-releasing peptide; TLR; interleukin; protein kinase A; HbA1c; LDLR; VASP; APCs; NK cells; GLP-1; Inflammation; glucose-dependent insulinotropic peptide; CCL; ECM; growth-hormone-releasing factor; natural killer cells; B-type natriuretic peptide; FAP; GHRF; adenosine deaminase; EPC; CD26; toll-like receptor; hemoglobin A1c; ADA; extracellular matrix; homeostasis model assessment beta cell function index; Endocrinopathy; Enzyme; Metabolic diseases; Cardiovascular disease; Glucose; Vascular disease; Peptidases; Hydrolases
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2012.09.012

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.