Pleiotropic effects of the dipeptidylpeptidase-4 inhibitors on the cardiovascular system

Abstract

Dipeptidylpeptidase-4 (DPP-4) is a ubiquitously expressed transmembrane protein that removes NH2-terminal dipeptides from various substrate hormones, chemokines, neuropeptides, and growth factors. Two known substrates of DPP-4 include the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide, which are secreted by enteroendocrine cells in response to postprandial hyperglycemia and account for 60–70% of postprandial insulin secretion. DPP-4 inhibitors (DPP-4i) block degradation of GLP-1 and gastric inhibitory peptide, extend their insulinotropic effect, and improve glycemia. Since 2006, several DPP-4i have become available for treatment of type 2 diabetes mellitus. Clinical trials confirm that DPP-4i raises GLP-1 levels in plasma and improves glycemia with very low risk for hypoglycemia and other side effects. Recent studies also suggest that DPP-4i confers cardiovascular and kidney protection, beyond glycemic control, which may reduce the risk for further development of the multiple comorbidities associated with obesity/type 2 diabetes mellitus, including hypertension and cardiovascular disease (CVD) and kidney disease. The notion that DPP-4i may improve CVD outcomes by mechanisms beyond glycemic control is due to both GLP-1-dependent and GLP-1-independent effects. The CVD protective effects by DPP-4i result from multiple factors including insulin resistance, oxidative stress, dyslipidemia, adipose tissue dysfunction, dysfunctional immunity, and antiapoptotic properties of these agents in the heart and vasculature. This review focuses on cellular and molecular mechanisms mediating the CVD protective effects of DPP-4i beyond favorable effects on glycemic control.

Fig. 1.

Pleiotropic effects of dipeptidylpeptidase-4 (DPP-4) inhibitors (DPP-4i) that benefit the vasculature. DPP-4i exhibit multiple protective effects that collectively contribute to improvement in vascular function which can reduce the risk for development of vascular disease, heart failure, and chronic kidney disease. In the setting of obesity/type 2 diabetes mellitus, circulating DPP-4 levels are elevated, due in part to elevated secretion of DPP-4 from inflamed visceral fat. Preclinical and clinical studies examining the efficacy of the DPP-4i have shown improvement in a number of cardiovascular disease (CVD) outcomes, as indicated in the gray boxes. SDF-1α, stromal cell-derived factor 1α; CXCR-4, C-X-C chemokine receptor type 4; BNP, brain natriuretic peptide; BP, blood pressure; GLP-1, glucagon-like peptide-1; MMP, matrix metalloproteinase; AP-1, activator protein-1; PTC, proximal tubule cell; EPC, endothelial progenitor cell.

Fig. 2.

DPP-4 biology and pharmacology of DPP-4i. Incretin hormones, GLP-1, and gastric inhibitory peptide (GIP) regulate insulin secretion in a glucose-dependent manner. DPP-4i inhibit degradation of GLP-1 and GIP, thereby contributing to glycemic control. However, DPP-4i will have multiple effects beyond glycemic control that occur by GLP-1-independent mechanisms because of wide substrate specificity and direct effects of DPP-4 with other proteins. GLP-1R, GLP-1 receptor; I/R, ischemia-reperfusion; MI, myocardial infarction; NPY-1, neuropeptide Y-1; VSMC, vascular smooth muscle cell.

Fig. 3.

A schematic representation depicting deleterious effects of overnutrition and obesity in the vasculature and targets for DPP-4i. Numbered black circles 1 through 13 indicate key components of pathology. DPP-4i improve vascular dysfunction through GLP-1-dependent and -independent mechanisms through modulation of insulin (1) and renin-angiotensin-aldosterone system (RAAS) activation (2) leading to state of reactive oxygen species (ROS)-induced ROS and mitochondrial ROS amplification (3) and endoplasmic reticular (ER) stress (4). Advanced glycation end products (AGE) (5), hyperglycemia (6), and low-grade endotoxemia (7) collectively contribute to intracellular oxidative stress. The exacerbated state of oxidative stress induces activation of redox sensitive kinases that influence the phosphorylation state of insulin receptor substrate-1 (IRS-1) to reduce nitric oxide (NO) generation via the phosphoinositide 3-kinase (PI3K)/Akt/endothelial NO synthase (eNOS) signaling pathway while favoring signaling through the Shc Ras/MEK/MAPK to increase synthesis of endothelin-1 (ET-1). GLP-1 mediated activation of eNOS (8) and cAMP responsive element binding protein (CREB) (9) also contribute to vascular protection by DPP-4i. Dyslipidemia (10) and dysfunctional immunity (11) and dysfunctional visceral and perivascular adipose tissue (12) further contribute to vascular injury and inflammation. Thus the interaction of vascular cells, immune cells and adipose tissue causes abnormalities in vascular function and remodeling (13). DPP-4i (indicated by yellow boxes) modulate different components of pathways that could act to improve vascular function. RAGE, receptor for AGE; TLR, Toll-like receptor; Treg, regulatory T cells; Th, T-helper cells; WBC, white blood cell; MCP-1, monocyte chemoattractant protein-1; Ox-LDL, oxidized LDL; NOX, NADPH oxidase; AT₁R, angiotensin type 1 receptor; MR, mineralocorticoid receptor; EC, endothelial cell; Ets-1, E26 transformation-specific-1; Ser P, serine phosphorylation; Tyr P, tyrosine phosphorylation; PDK1, 3-phosphoinositide-dependent protein kinase-1; AMPK, AMP-activated protein kinase; AC, adenylate cyclase; HO-1, hemoxygenase-1; NQQ1, quinine reductase.

Fig. 4.

DPP-4i facilitates endothelial repair, plaque stabilization, and neovascularization by preventing the degradation of its substrate, SDF-1α, which recruits bone marrow derived EPCs to injured areas of the endothelium.