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Cells 2018, 7(10), 181; https://doi.org/10.3390/cells7100181

Review
Is there a Chance to Promote Arteriogenesis by DPP4 Inhibitors Even in Type 2 Diabetes? A Critical Review
1
MedGenome Labs Ltd., Bangalore, Karnataka 560099, India
2
School of Chemical Biotechnology, SASTRA University, Thanjavur 613401, India
3
Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, 80336 Munich, Germany
*
Author to whom correspondence should be addressed.
Received: 13 August 2018 / Accepted: 18 October 2018 / Published: 22 October 2018

Abstract

:
Cardiovascular diseases (CVD) are still the prevailing cause of death not only in industrialized countries, but even worldwide. Type 2 diabetes mellitus (type 2 DM) and hyperlipidemia, a metabolic disorder that is often associated with diabetes, are major risk factors for developing CVD. Recently, clinical trials proved the safety of gliptins in treating patients with type 2 DM. Gliptins are dipeptidyl-peptidase 4 (DPP4/CD26) inhibitors, which stabilize glucagon-like peptide-1 (GLP-1), thereby increasing the bioavailability of insulin. Moreover, blocking DPP4 results in increased levels of stromal cell derived factor 1 (SDF-1). SDF-1 has been shown in pre-clinical animal studies to improve heart function and survival after myocardial infarction, and to promote arteriogenesis, the growth of natural bypasses, compensating for the function of an occluded artery. Clinical trials, however, failed to demonstrate a superiority of gliptins compared to placebo treated type 2 DM patients in terms of cardiovascular (CV) outcomes. This review highlights the function of DPP4 inhibitors in type 2 DM, and in treating cardiovascular diseases, with special emphasis on arteriogenesis. It critically addresses the potency of currently available gliptins and gives rise to hope by pointing out the most relevant questions that need to be resolved.
Keywords:
cardiovascular disease (CVD); arteriogenesis; diabetes mellitus; dipeptidyl-peptidase-4 (DPP4) inhibitors; stromal-cell-derived factor-1 (SDF-1); gliptins

1. Introduction

Cardiovascular diseases (CVD), such as coronary heart disease, cerebrovascular disease, and peripheral artery disease, are still the major cause of morbidity and death worldwide. For 2030, the World Health Organization (WHO) projected around 23 million deaths due to CVD [1]. Hyperlipidemia and diabetes mellitus are major risk factors for CVD by increasing atherosclerosis [2]. Moreover, collateral artery growth (arteriogenesis), which compensates for the functional loss of an artery due to atherosclerosis, is compromised in diabetes [3,4], a disease which is often associated with hyperlipidemia (see below). Accordingly, there is a pressing need for effective drugs to treat CVD, which also show positive effects in patients with diabetes, even with insulin resistance. In particular, these drugs should have the capacity to promote arteriogenesis, which is a tissue-, and even life-saving, process. Dipeptidyl-peptidase 4 (DPP4/CD26) inhibitors might present such drugs.

2. Arteriogenesis

The detrimental consequences of arterial stenosis, such as stroke, myocardial infarction, or peripheral artery disease, are a huge burden for affected patients worldwide. Occlusion of main blood conducting arteries results in severe ischemic damage of distal tissue, which might not be only associated with tissue damage, but even death. However, in the clinic, it is repeatedly observed that patients with occluded arteries show only minimal symptoms. These patients profited from arteriogenesis as a response to slow progressive stenosis [5]. Our whole body, not only the brain and the heart, but also the periphery, is pervaded with a collateral artery network. Upon slow progression of stenosis formation, blood flow is redirected into pre-existing collateral arteries bypassing the stenosing artery. Due to the increased blood flow, the endothelial cells of detouring arterioles experience elevated mechanical load, i.e. fluid shear stress [6], leading to their activation [7]. In contrast to angiogenesis, which is defined as the sprouting of capillaries, collateral artery growth not only involves the proliferation of endothelial cells, but also of smooth muscle cells. Recently, a mechanosensory complex consisting of vascular endothelial growth factor receptor 2 (VEGFR2), platelet endothelial cell adhesion molecule (PECAM)-1, and the adaptor protein vascular endothelial cell cadherin (VE-cadherin) has been identified [8]. It has been discussed for a long time whether the VEGFR2 ligand, vascular endothelial growth factor-A (VEGF-A), plays a role in arteriogenesis [9]. Whereas blocking of VEGFR2 significantly interfered with the process of arteriogenesis, administration of VEGF-A showed only little or no effect. We were recently able to show that the process of collateral artery growth is associated with elevated levels of VEGF-A [10], and that these levels of VEGF-A are not only necessary, but also sufficient to drive arteriogenesis. Accordingly, application of VEGF-A will not further promote the growth of collaterals, whereas blocking its cognate receptor, VEGFR2, dramatically interferes with vessel growth. As endothelial cells do not produce VEGF-A [11], the question arises, what is the source of VEGF-A. The endothelial glycocalyx consists of hyaluronic acid, glycoproteins, and proteoglycans, conferring it a negative charge. In the extended endothelial cell surface layer, plasma proteins and growth factors, among them VEGF-A, are stored [12]. Due to locally increased fluid shear stress, VEGF-A binds to VEGFR2, which involves Neuropilin-1 amplifying VEGFR2 signaling [13]. Thereupon, probably several cascades become activated in endothelial cells. Amongst them, the phosphatidylinositide 3-kinases (PI3K)/Akt pathway is relevant for increased expression levels of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS). Both isoforms are relevant for endothelial cell proliferation and are likely able to substitute for each other [10]. Moreover, VEGFR2/Neuropilin-1 signaling has been engaged in releasing the major ligand of the platelet receptor glycoprotein 1bα (GPIbα), the van Willebrand factor (vWF), from endothelial cells [14]. In recent investigations, we have demonstrated that GPIbα is essential for transient interaction of platelets with the endothelium [15], which is likely to trigger surface expression of P-selectin on platelets [16]. Upon binding of P-selectin to P-selectin glycoprotein ligand 1 (PSGL-1) on neutrophils, platelet-neutrophil aggregates (PNAs) are formed, resulting in neutrophil-NADPH oxidase 2 (Nox2) activation and translocation of urokinase plasminogen activator (uPA) on the surface of neutrophils [17]. Neutrophil uPA, together with endothelial cell uPA, whose expression is increased during the process of arteriogenesis [18], are relevant for paracellular transmigration and extravasation of neutrophils [19]. In the perivascular space, reactive oxygen species (ROS)- derived from neutrophil Nox-2 activate mast cells [17]. Mast cells, in turn, recruit further neutrophils by increasing the bioavailability of tumor necrosis factor α (TNF α). Neutrophils are a rich source of VEGF-A, the expression and release of which is mediated by midkine [10], enforcing VEGF-A signal transduction cascades resulting in endothelial cell proliferation and mast cell activation. In addition to neutrophils, activated mast cells also recruit T cells [17]. Moreover, by increasing the bioavailability of monocyte chemoattractant protein-1 (MCP-1), they recruit monocytes to the perivascular space [17]. Upon maturation to macrophages, these cells supply a variety of cytokines and growth factors—among them VEGF-A—to the growing vessel [20,21]. Altogether, arteriogenesis is a local inflammatory process, in which mast cells play an essential role by recruiting growth promoting leukocytes.
Angiogenesis is also a local inflammatory process [22]. Whereas capillaries have the function to provide oxygen and metabolites for tissues locally, arteries transport oxygenated blood through the body. Accordingly, only arteriogenesis, the growth of pre-existing arteriolar connections to functional arteries, is capable to compensate for the loss an artery (Figure 1).
Patients with diabetes show a high prevalence of high-grade coronary atherosclerosis [23]. Unfortunately, in these patients, the growth of compensating coronary collateral arteries is severely impaired [24]. Peripheral artery disease is also a common complication in type 2 diabetes mellitus (type 2 DM) [25]. It is associated with lower extremity function, critical limb ischemia, and foot ulceration [26,27], and, due to impaired arteriogenesis [28], with limb amputation [29]. The long-term prognosis of patients with DM and peripheral artery disease is extremely poor, with a high mortality rate [30].

3. Glucose Uptake and the Metabolic Disorder Diabetes Mellitus

3.1. Incretins, Insulin, and the Adrenergic System

Glucose in chyme stimulates the release of the metabolic hormones, gastric inhibitory polypeptide (GIP) and glucose-dependent insulinotropic peptide-1 (GLP-1), from intestinal mucosa. Thereupon, these incretins augment the secretion of insulin, a polypeptide hormone, which is produced by beta cells of the pancreatic islets. This endocrine pancreatic activity is reciprocally regulated by the adrenergic system. While activation of the β2-adrenoreceptor (β2-AR) promotes insulin release [31], it is repressed when the α2-AR becomes activated [32]. In the blood, insulin reduces the blood glucose levels by stimulating cells to absorb glucose from the blood. Again, this process is potentiated through activation of β2-AR by adrenaline [33] and antagonized by noradrenergic α1-AR stimulation [34,35]. Moreover, insulin is a functional opponent of glucagon. Glucagon is a peptide hormone, which is released from the pancreas to the bloodstream upon stimulation of β-adrenergic receptors mainly due to hypoglycemia, protein rich food, and stress. In the liver, glucagon stimulates gluconeogenesis and glycogenolysis, resulting in increased blood glucose levels. Insulin and GLP-1 inhibit glucagon secretion, resulting in reduction of blood glucose levels. Binding of insulin to its receptor results in cross-talk with β2-AR, and β2-AR gene deletion results in hepatic insulin resistance [36]. Increased prevalence of insulin resistance in elderly patients with type 2 diabetes mellitus has been related to reduced expression of β2-AR [31,37,38]. Resistance to insulin is characterized by defects in muscle glucose uptake and hepatic glucose overproduction.
The adrenergic system has also been implicated in angiogenesis. While stimulation of α1-AR interfered with endothelial cell proliferation, migration, and tube formation, antagonizing the receptor showed the opposite effect. Moreover, blocking the receptor resulted in enhanced extracellular signal regulated kinase (ERK) activation and retinoblastoma phosphorylation, relevant for cell proliferation [39]. Deficiency of the β2-AR on endothelial cells, in contrast, impaired nuclear factor ‘kappa-light-chain-enhancer’ (NF-κB) activation and tube formation in vitro and angiogenesis in vivo [40]. However, further investigations are necessary to define the exact molecular mechanisms and signal transduction cascades associated with adrenoreceptor signaling in endothelial cells.

3.2. Diabetes Mellitus and Glucose-Dependent Insulinotropic Peptide-1 (GLP-1)

Diabetes mellitus refers to a metabolic disorder resulting in high blood glucose levels due to either reduced insulin levels caused by destruction of insulin-producing beta-cells (type 1 DM), or insulin resistance (type 2 DM). Out of the two, type 2 DM is the prevailing form, with 95% of all DM cases being type 2 [41]. Moreover, about 85% of type 2 DM exhibit insulin resistance [42]. Besides hyperlipidemia, DM is a major risk factor for coronary and peripheral artery diseases [2].
Increasing insulin resistance elicits increased levels of free fatty acids in the blood. Accordingly, hyperglycemia in type 2 DM is often associated with hyperlipidemia, a metabolic disorder, which is characterized by high concentrations of triglycerides and low-density lipoprotein (LDL) cholesterol in the blood. Besides its action on insulin release, GLP-1 also regulates cholesterol and triglycerides. It reduces VLDL triglyceride production in the liver and regulates reverse cholesterol transport [43,44,45,46,47,48]. GLP-1 as well as GIP are rapidly inactivated by the enzyme, DPP4 [49], whose activity correlates with insulin resistance in type 2 DM [50,51].
Whether GLP-1 acts on hepatocytes, thereby directly exerting a function in the liver, is controversially discussed. Although there are data available showing the expression of the GLP-1 receptor (GLP-1R) on hepatocytes [52], these results were not confirmed by others [53]. As insulin resistance is a common problem in patients with type 2 DM, it is of major importance to clarify whether GLP-1 and, accordingly, GLP-1-based drugs (GLP-1 analogues, see below) have the capacity to exert their beneficial effects not only indirectly via insulin and glucagon, but also directly by binding the GLP-1R on hepatocytes. When treating healthy subjects with GLP-1 (45 pmol/kg per h), D’Alessio et al. found that GLP-1 improves glucose tolerance, and suggested that this is due to stimulation of insulin release and of insulin-independent glucose disposal [54]. In contrast, by infusing physiological postprandial levels of GLP-1 (0.4 pmol/kg per min), Seghieri et al. found a reduction in hepatic glucose production, but no effect on glucose disposal, and concluded that GLP-1 either directly inhibits hepatic gluconeogenesis or has a neutral effect [55]. Since GLP-1 is rapidly degraded by DPP4, it is not suitable as a drug to treat patients. Accordingly, DPP4–resistant mimetics of GLP-1 have been developed. These include exenatide [56], which is the synthetic form of the naturally occurring peptide, exendin-4 [57]. Interestingly, exendin-4 has been described to increase glucokinase enzyme activity in the liver independent of insulin (probably by acting on the hepatic GLP-1R) [58] and to improve insulin sensitivity [59]. For the latter, several mechanisms are discussed [60,61,62,63,64]. Since GLP-1 analogues are not applicable orally, non-peptide agonists would be desirable, which do not require self-injection by patients.
Recently, it has been shown that GLP-1 also stimulates nitric oxide (NO) production, thereby reducing blood pressure and the risk of atherosclerosis [65]. Indeed, it has been described that endothelial NO synthase (eNOS) is uncoupled in type 2 DM, thereby resulting in decreased levels of NO [66,67,68]. Interestingly, it has been demonstrated that blocking DPP4 activity gives rise to increased NO production, even independent of GLP-1, by promoting phosphorylation of endothelial NO synthase (eNOS) [69]. Orally applicable DPP4 inhibitors are currently used to treat type 2 DM (see below).

4. Molecular Functions of Dipeptidyl-Peptidase-4 (DPP4)

Proteases are involved in all kinds of physiological and pathophysiological processes, such as inflammation, fertilization, cell proliferation and death, tumor growth, and tissue remodeling [70]. DPP4 belongs to a class of specialized proteases, which cleave proline adjacent bonds. These proteases consist of (1) metallopeptidases, such as aminopeptidase P, carboxypeptidase P, and prolidase; and (2) three serine proteases, i.e. prolyloligopeptidase, DPP2, and DPP4 [70]. DPP4 belongs to prolyloliogopeptidases, which have evolved by independent convergent evolution [71,72]. A number of DPP4-like proteins are identified, which show either similarity to DPP4 activity, or are structurally related to DPP4, but enzymatically inactive. These proteins are called DPP4 activity and/or structure homologues (DASH) [73] and, for example, include fibroblast activation protein (FAP) [74], DPP4b [75], DPP6 [76], DPP7 [77], and DPP8 [78].
DPP4 is an intrinsic membrane glycoprotein that cleaves X-proline dipeptides from the N-terminus of polypeptides, however, it also exists in a soluble form [79]. Thus, DPP4 plays a major role in the regulation and activation of paracrine and autocrine as well as of extracellular endocrine peptides [80]. The protein is expressed in a variety of cells, although mainly in adipocytes [51], macrophages [81], T cells [82], endothelial cells [83], epithelial cells [84], and hepatocytes [85].
Beyond glucose control, DPP4 has a variety of functions, and not all of them are mediated by the enzymatic activity of the protein. The extracellular domain, which is involved in adenosine deaminase (ADA)/extracellular matrix binding, is exclusively responsible for the enzymatic activity of the enzyme [86]. Besides cleaving GLP-1 and GIP, both of which stimulate insulin secretion (see above), DPP4 also cleaves the regulatory peptides, glucagon-like peptide-2 (GLP-2), which plays a part in intestinal growth and function [87]; gastrin-releasing peptide (GRP) [88], which is involved in gastric acid secretion; and growth-hormone-releasing factor (GHRF), which stimulates growth hormone production [89]. However, DPP4 also modifies neuropeptides enzymatically. Among them are B-type natriuretic peptide (BNP), playing a role in vasodilation [90]; substance P, a neurotransmitter [91]; peptide YY, which is involved in electrolyte absorption in the colon [92]; and neuropeptide Y (NPY), which is linked to learning and memory [93]. Moreover, DPP4 cleaves a variety of chemokines, which are all involved in chemotaxis and leukocyte recruitment, including interferon-inducible T cell α chemoattractant (ITAC) [94], interferon-γ-induced protein-10 (IP-10) [94], Eotaxin [95], monokine induced by interferon γ (MIG) [96], macrophage derived chemokine (MDC) [97], regulated on activation normal T cell expressed and presumably secreted (RANTES) [98], granulocyte colony stimulating factor (G-CSF) [99], granulocyte monocyte colony stimulating factor (GM-CSF) [99], and stromal-cell-derived factor-1 (SDF-1) [94]. For an overview of the DPP4 mediated effects see Table 1.
Besides its enzymatic activity, DPP4 can interact with several other ligands. By binding to adenosine deaminase (ADA) [100], caveolin-1 [101], insulin growth factor receptor 2 (IGFR2) [102], and protein tyrosine phosphatase receptor type C (PTPRC, D45) [103], DPP4 positively regulates T cell co-activation. Moreover, it triggers T cell proliferation by binding to caveolin-1 and caspase recruitment domain-containing protein 11 (CARD11) [101]. It also promotes the proteolysis of the extracellular matrix and the migration of endothelial cells by interacting with separase [104]. Furthermore, DPP4 induces CD68 upregulation on monocytes by binding to caveolin-1 [105]. By associating with the Na+-H+ ion exchanger isoform sodium–hydrogen exchanger 3 (NHE3), DPP4 has been suggested to regulate NH3 activity and surface expression [106], and it is postulated that DPP4 also interacts with the thromboxane A2 receptor [107].

5. Cardiovascular Functions of Stromal-Cell-Derived Factor-1

The substrate of DPP4 SDF-1/CXCL12 plays a particularly important role in the cardiovascular system (see below). By interacting with its receptor, CXC-motive-chemokine receptor 4 (CXCR4), SDF-1 recruits leukocytes, such as neutrophils, monocytes, T-, and B cells, as well as other bone marrow derived CXCR4+ cells, such as stem cells and mast cells [17]. Askari et al. described SDF-1 as a key regulator involved in the homing of stem cells to ischemic myocardium, and showed that SDF-1 levels are already upregulated one hour after myocardial infarction, but return to baseline levels seven days later [108]. In rodent models, it was shown that overexpression of SDF-1 improved myocardial function after infarction and promoted revascularization [109,110]. Zhang et al. have shown that stem cells are not involved in the regeneration of cardiac myocytes after myocardial infarction, but that they play a beneficial paracrine role in cardiac myocyte survival and vascularization by supplying SDF-1 [111].
As SDF-1 is cleaved and hence inactivated by DPP4 [112], it was suggested that inhibition of DPP4 activity and thus stabilization of SDF-1 might be a promising approach to treat cardiovascular and peripheral artery diseases (for an example see Figure 2).

6. DPP4 Inhibitors and Cardiovascular Diseases

6.1. DPP4 Inhibitors in Pre-Clinical Studies

Particularly due to the function of SDF-1 to recruit bone marrow derived cells, DPP4 inhibitors have been used to increase SDF-1 levels, aiming to improve CVD in pre-clinical animal studies. In several studies, the DPP4 inhibitor, Diprotin A, which is administered intraperitoneally (i.p.), has been applied. Referring to the studies of Christopherson et al. [112], who showed that Diprotin A increased the transmigration of progenitor cells towards an SDF-1 gradient, Zaruba et al. [113] performed studies in a murine model of myocardial infarction. This investigation showed that Diprotin A treatment decreased DPP4 activity in the myocardium (but not in the serum), which was associated with increased levels of SDF-1 and homing of CXCR-4+ stem cells, finally resulting in reduced cardiac remodeling, increased neovascularization, and improved myocardial function and survival. Similar results were obtained by Dingenouts et al. [114], who moreover showed that Diprotin A treatment results in a shift towards regenerative M2 macrophages in infarcted myocardium. We performed studies on a murine hindlimb model of arteriogenesis, a shear stress triggered process that relies on local recruitment of leukocytes, which promote the proliferation of endothelial- and smooth muscle cells of pre-existing collateral arterioles, finally resulting in natural bypass growth [5]. Our studies demonstrated that Diprotin A treatment increased SDF-1 levels in collaterals (but not in serum), which resulted in increased mast cell recruitment. In turn, mast cell recruited leukocytes (neutrophils, T cells, and macrophages) significantly enhanced arteriogenesis [17]. Using the same model of arteriogenesis, although with sitagliptin as a DPP4 inhibitor, Haverslag et al. also found an improved perfusion recovery in atherosclerosis prone ApoE-/- mice [115]. Interestingly, their results suggested that DPP4 inhibition showed no adverse side effects on atherogenesis and might even contribute to plaque stability. In accordance with our study, Haverslag et al. observed an increased accumulation of macrophages in the perivascular space of growing collaterals. Moreover, their results demonstrated an increased expression of the monocyte activation marker, CD11b, and of the SDF-1 receptor, CXCR-4, relevant for leukocyte activation and transmigration through activation of lymphocyte function-associated antigen-1 (LFA-1), and of very late antigen-4 and -5 (VLA-4, VLA-5) [116] on circulating monocytes. However, enhanced SDF-1 mediated CXCR-4 activation is also likely to induce NF-κB signaling in leukocytes [117] as well as phosphatidylinositol 3-kinase (PI3K), p44/42 mitogen-activated protein kinase (Erk 1 and Erk 2) [117], transforming growth factor-β (TGF-β), and tumor necrosis factor-α (TNF-α) [118] signaling in vascular cells, which are all relevant for effective collateral artery growth [10,119,120,121,122]. In a parallel study, it was shown by Krieger et al. that hydrogels locally releasing SDF-1 supported sustained natural bypass growth by recruiting M2 polarized macrophages [123], which have been shown to enhance arteriogenesis by promoting vascular remodeling [124]. This is an interesting finding, since Brenner et al. showed that sitagliptin treatment of mice (see below) mitigated atherosclerosis by priming monocytes into M2 macrophages [125]. Accordingly, these results strengthen the findings of Haverslag on atherogenesis in the mouse model of arteriogenesis in ApoE-/- mice.
In recent investigations, we were able to show that insulin treatment rescued arteriogenesis in streptozotocin-induced type 2 DM in mice by restoring leukocyte recruitment (unpublished own data). These data give rise to hope for treatment of type 2 DM patients with vascular occlusive diseases. Since the stabilization of GLP-1 through DPP4 inhibitors resulted in increased bioavailability of and sensitivity to insulin [126], and since DPP4 inhibitors have a positive effect on hypercholesterolemia, which also interferes with arteriogenesis [127], DPP4 inhibitors might not only restore arteriogenesis in type 2 DM patients, but even enhance it due to the local increase of SDF-1 levels. Moreover, DPP4 inhibitors evoked increased bioavailability of NO, relevant for proper arteriogenesis [10], which might also contribute to beneficial effects. Since G-CSF and GM-CSF are also substrates of DPP4, blocking its activity might additionally promote arteriogenesis since both factors were shown to enhance collateral artery growth when administered exogenously [128,129]. The importance of arteriogenesis has recently been demonstrated in a meta-analysis showing that high collateralization in patients with coronary artery disease (CAD) is associated with a 36% reduction of mortality risk [130]. Promoting natural bypass growth by drugs presents an elegant and non-invasive alternative to current clinical interventions, such as percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), and bypass transplantation.

6.2. DPP4 Inhibitors in Clinical Studies

As DDP4 inhibitors represent a promising tool to treat patients with type 2 DM, several clinical studies were performed (for a short overview see Table 2). As diprotin A cannot be used for treating patients [131], other orally applicable DPP4 inhibitors, so-called gliptins, were applied. First results of meta-analyses of randomized controlled trials (RCTs), such as TECOS (Trial Evaluating Cardiovascular outcomes with Sitagliptin) [132], SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Type 2 Diabetes Mellitus) [133], or EXAMINE (Examination of Cardiovascular Outcomes: Alogliptin vs. Standard Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome) [134], displayed a trend toward a lower incidence of major cardiovascular events (MACE), paving the way for further studies (recently reviewed in [135]).
All the subsequent trials showed that DPP4 inhibitors have a good safety profile. Due to the positive effects of DPP4 inhibitors on angiogenesis and arteriogenesis shown in pre-clinical studies, one would expect detrimental effects on retinopathy and nephropathy, which are caused by excessive vascularization [137] and are highly prevalent in patients with type 2 DM [137,138,139]. Yet the opposite was the case. Several clinical studies reported retino- as well as renoprotective effects of DPP4 inhibitors [140,141,142,143]. However, in terms of CVD, DPP4 inhibitors were not superior compared to placebo. This may be explained by several facts: (1) The trials were primarily designed to prove the safety of DPP4 inhibitors and not their superiority in terms of CVD outcomes; (2) the duration of these studies was probably too short (two to three years) to show any differences in CV (cardiovascular) outcomes; (3) that the positive effect in some patient subgroups may be compensated by zero (or even negative) outcomes in other subgroups. At this point, it is relevant to mention that the first trials only included patients with a rather low risk of CVD. Accordingly, the number of patients with surgical interventions, such as PTCA or intensive pharmacological treatment, was very low. This is an important point in terms of arteriogenesis. When the process of stenosis occurs (very slowly), the blood flow is redirected into pre-existing collateral arteries, triggering them to grow. However, if the stenotic artery is re-vascularized by PTA or PTCA, growing or grown collaterals are degraded as they are not needed anymore. Moreover, drugs, such as, for example, angiotensin-converting enzyme inhibitors, which degrade SDF-1 [144], might interfere with the positive effect of DPP4 inhibitors in arteriogenesis. Accordingly, new analyses are necessary, which take surgical and pharmacological treatment of patients into account; furthermore (4) the dose as well as the administration route might play a role. Recent studies on animal models using sitagliptin, which has been shown to be safe in the TECOS study, addressed this point (see Section 6.3).

6.3. DPP4 Inhibitors Revisited in Pre-Clinical Studies

Sitagliptin is administered orally in patients at a dose of 100 mg/d. The bioavailability is 87%, but 79% of the drug is excreted unchanged in the urine. Theiss et al. [145] performed a study on outcomes of myocardial infarction in mice using different dosages of orally administered sitagliptin ranging from 5 mg/kg/d to 500 mg/kg/d, and showed that only the treatment with 500 mg/kg significantly reduced DPP4 activity in the blood, whereby significantly increased numbers of bone marrow derived cells homing in the myocardium after infarction were already observed at a dose of 50 mg/kg. Treatment regimens with 500 mg/kg/d resulted in significantly reduced cardiac remodeling, increased capillary density, and improved myocardial function and survival of mice. The same results were obtained when the DPP4 inhibitor, vildagliptin, was used at an equal dosage. Brenner and co-workers, who also used 500 mg/kg/d of sitagliptin for oral treatment of mice, reported ameliorated atherosclerosis based on priming monocytes into M2 macrophages [125]. Moreover, they demonstrated that SDF-1, independent of GLP-1 action, shows a direct proliferative effect on endothelial cells [146], a process that is decisive for arteriogenesis [147].
Ghorpade et al. [148], recently published a study showing that oral administration of 35–40 mg/kg/d of sitagliptin significantly decreased plasma DPP4 activity in diet-induced obese (DIO) mice. The same result was obtained when mice were treated intravenously (i.v.) with a short hairpin RNA (shRNA) that specifically silenced DPP4 in the liver. However, in contrast to orally administered sitagliptin, only liver specific silencing of DPP4 decreased liver DPP4 protein levels and hepatocyte DPP4 activity.
Moreover, liver specific silencing of DPP4 lowered plasma insulin, improved glucose uptake, and suppressed insulin resistance in DIO mice. These data are in accordance with studies reporting that oral DPP4 inhibitors do not lower plasma insulin in insulin-resistant, hyperinsulinemic patients [149,150,151,152,153,154]. These facts throw a completely new light on orally administered DPP4 inhibitors in patients with type 2 DM in terms of rescuing or even enhancing the process of arteriogenesis. Several questions thus need to be addressed in pre-clinical studies.

6.4. Questions

As oral DPP4 inhibitors do not suppress insulin resistance, the first question is whether this is due to the oral application form or due to the dosage. GLP-1 receptor agonists, such as exenatide or semaglutide, used to increase insulin sensitivity in patients, are administered subcutaneously [155,156]. DPP4 increases insulin resistance by enzymatically cleaving GLP-1. However, it still remains to be elucidated whether insulin sensitivity is additionally promoted by a non-enzymatic function of DPP4. Therefore, the question arises of whether gliptins really are the best choice to treat insulin resistance. Another question is whether gliptins work equally well in rodents and humans concerning the specific recognition of DPP4 or whether differences in efficacy are due to differences in species. The next question is whether currently available DPP4 inhibitors reach all desired target organs (including the liver). Accordingly, the final question arises: Do we have to develop a new class of DPP4 inhibitors? Last, but not least, the data on patients in terms of improvements of CVD need to be (re-)addressed, considering whether the overall surgical and pharmacological treatment of each subject might interfere with the process of arteriogenesis.

7. Conclusions

DPP4 inhibitors have been shown to be safe in clinical trials and might efficiently promote arteriogenesis even in patients with type 2 DM. However, several problems need to be resolved before we will be able to efficiently promote arteriogenesis even in patients with type 2 DM.

Author Contributions

S.V., A.-K.K. and E.D. wrote the article.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. World-Health-Organisation. Cardiovascular Diseases (cvds); World-Health-Organisation: Geneva, Switzerland, 2013. [Google Scholar]
  2. Kannel, W.B.; McGee, D.L. Diabetes and cardiovascular disease. The Framingham study. JAMA 1979, 241, 2035–2038. [Google Scholar] [CrossRef] [PubMed]
  3. Abaci, A.; Oguzhan, A.; Kahraman, S.; Eryol, N.K.; Unal, S.; Arinc, H.; Ergin, A. Effect of diabetes mellitus on formation of coronary collateral vessels. Circulation 1999, 99, 2239–2242. [Google Scholar] [CrossRef] [PubMed]
  4. Rivard, A.; Silver, M.; Chen, D.; Kearney, M.; Magner, M.; Annex, B.; Peters, K.; Isner, J.M. Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adeno-VEGF. Am. J. Pathol. 1999, 154, 355–363. [Google Scholar] [CrossRef]
  5. Deindl, E.; Schaper, W. The art of arteriogenesis. Cell Biochem. Biophys. 2005, 43, 1–15. [Google Scholar] [CrossRef]
  6. Lasch, M.; Nekolla, K.; Klemm, A.H.; Buchheim, J.I.; Pohl, U.; Dietzel, S.; Deindl, E. Estimating hemodynamic shear stress in murine peripheral collateral arteries by two-photon line scanning. Mol. Cell. Biochem. 2018. [Google Scholar] [CrossRef] [PubMed]
  7. Pipp, F.; Boehm, S.; Cai, W.J.; Adili, F.; Ziegler, B.; Karanovic, G.; Ritter, R.; Balzer, J.; Scheler, C.; Schaper, W.T.S.-R. Elevated fluid shear stress enhances postocclusive collateral artery growth and gene expression in the pig hind limb. Arterioscler. Thromb. Vasc. Biol. 2004, 24, 1664–1668. [Google Scholar] [CrossRef] [PubMed]
  8. Tzima, E.; Irani-Tehrani, M.; Kiosses, W.B.; Dejana, E.; Schultz, D.A.; Engelhardt, B.; Cao, G.; DeLisser, H.; Schwartz, M.A. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 2005, 437, 426–431. [Google Scholar] [CrossRef] [PubMed]
  9. Jazwa, A.; Florczyk, U.; Grochot-Przeczek, A.; Krist, B.; Loboda, A.; Jozkowicz, A.; Dulak, J. Limb ischemia and vessel regeneration: Is there a role for VEGF? Vasc. Pharmacol. 2016, 86, 18–30. [Google Scholar] [CrossRef] [PubMed]
  10. Lautz, T.; Lasch, M.; Borgolte, J.; Troidl, K.; Pagel, J.I.; Caballero-Martinez, A.; Kleinert, E.C.; Walzog, B.; Deindl, E. Midkine Controls Arteriogenesis by Regulating the Bioavailability of Vascular Endothelial Growth Factor A and the Expression of Nitric Oxide Synthase 1 and 3. EBioMedicine 2018, 27, 237–246. [Google Scholar] [CrossRef] [PubMed]
  11. Deindl, E.; Buschmann, I.; Hoefer, I.E.; Podzuweit, T.; Boengler, K.; Vogel, S.; van Royen, N.; Fernandez, B.; Schaper, W. Role of ischemia and hypoxia-inducible genes in arteriogenesis after femoral artery occlusion in the rabbit. Circ. Res. 2001, 89, 779–786. [Google Scholar] [CrossRef] [PubMed]
  12. Givens, C.; Tzima, E. Endothelial Mechanosignaling: Does One Sensor Fit All? Antioxid. Redox Signal. 2016, 25, 373–388. [Google Scholar] [CrossRef] [PubMed][Green Version]
  13. Kofler, N.M.; Simons, M. Angiogenesis versus arteriogenesis: Neuropilin 1 modulation of VEGF signaling. F1000Prime Rep. 2015, 7, 26. [Google Scholar] [CrossRef] [PubMed]
  14. Fischer, S.; Nishio, M.; Peters, S.C.; Tschernatsch, M.; Walberer, M.; Weidemann, S.; Heidenreich, R.; Couraud, P.O.; Weksler, B.B.; Romero, I.A.; et al. Signaling mechanism of extracellular RNA in endothelial cells. FASEB J. 2009, 23, 2100–2109. [Google Scholar] [CrossRef] [PubMed]
  15. Chandraratne, S.; von Bruehl, M.L.; Pagel, J.I.; Stark, K.; Kleinert, E.; Konrad, I.; Farschtschi, S.; Coletti, R.; Gartner, F.; Chillo, O.; et al. Critical role of platelet glycoprotein ibalpha in arterial remodeling. Arterioscler. Thromb. Vasc. Biol. 2015, 35, 589–597. [Google Scholar] [CrossRef] [PubMed]
  16. Goto, S.; Ichikawa, N.; Lee, M.; Goto, M.; Sakai, H.; Kim, J.J.; Yoshida, M.; Handa, M.; Ikeda, Y.; Handa, S. Platelet surface P-selectin molecules increased after exposing platelet to a high shear flow. Int. Angiol. 2000, 19, 147–151. [Google Scholar] [PubMed]
  17. Chillo, O.; Kleinert, E.C.; Lautz, T.; Lasch, M.; Pagel, J.I.; Heun, Y.; Troidl, K.; Fischer, S.; Caballero-Martinez, A.; Mauer, A.; et al. Perivascular Mast Cells Govern Shear Stress-Induced Arteriogenesis by Orchestrating Leukocyte Function. Cell Rep. 2016, 16, 2197–2207. [Google Scholar] [CrossRef] [PubMed][Green Version]
  18. Deindl, E.; Ziegelhoffer, T.; Kanse, S.M.; Fernandez, B.; Neubauer, E.; Carmeliet, P.; Preissner, K.T.; Schaper, W. Receptor-independent role of the urokinase-type plasminogen activator during arteriogenesis. FASEB J. 2003, 17, 1174–1176. [Google Scholar] [CrossRef] [PubMed]
  19. Reichel, C.A.; Uhl, B.; Lerchenberger, M.; Puhr-Westerheide, D.; Rehberg, M.; Liebl, J.; Khandoga, A.; Schmalix, W.; Zahler, S.; Deindl, E.; et al. Urokinase-type plasminogen activator promotes paracellular transmigration of neutrophils via Mac-1, but independently of urokinase-type plasminogen activator receptor. Circulation 2011, 124, 1848–1859. [Google Scholar] [CrossRef] [PubMed]
  20. Arras, M.; Ito, W.D.; Scholz, D.; Winkler, B.; Schaper, J.; Schaper, W. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J. Clin. Investig. 1998, 101, 41–50. [Google Scholar] [CrossRef] [PubMed]
  21. Morrison, A.R.; Yarovinsky, T.O.; Young, B.D.; Moraes, F.; Ross, T.D.; Ceneri, N.; Zhang, J.; Zhuang, Z.W.; Sinusas, A.J.; Pardi, R.; et al. Chemokine-coupled beta2 integrin-induced macrophage Rac2-Myosin IIA interaction regulates VEGF-A mRNA stability and arteriogenesis. J. Exp. Med. 2014, 211, 1957–1968. [Google Scholar] [CrossRef] [PubMed]
  22. Szade, A.; Grochot-Przeczek, A.; Florczyk, U.; Jozkowicz, A.; Dulak, J. Cellular and molecular mechanisms of inflammation-induced angiogenesis. IUBMB Life 2015, 67, 145–159. [Google Scholar] [CrossRef] [PubMed][Green Version]
  23. Goraya, T.Y.; Leibson, C.L.; Palumbo, P.J.; Weston, S.A.; Killian, J.M.; Pfeifer, E.A.; Jacobsen, S.J.; Frye, R.L.; Roger, V.L. Coronary atherosclerosis in diabetes mellitus: A population-based autopsy study. J. Am. Coll. Cardiol. 2002, 40, 946–953. [Google Scholar] [CrossRef]
  24. Weihrauch, D.; Lohr, N.L.; Mraovic, B.; Ludwig, L.M.; Chilian, W.M.; Pagel, P.S.; Warltier, D.C.; Kersten, J.R. Chronic hyperglycemia attenuates coronary collateral development and impairs proliferative properties of myocardial interstitial fluid by production of angiostatin. Circulation 2004, 109, 2343–2348. [Google Scholar] [CrossRef] [PubMed]
  25. American Diabetes Association. Peripheral Artery Disease in People with Diabetes. Diabetes Care 2003, 26, 3333–3341. [Google Scholar]
  26. Dolan, N.C.; Liu, K.; Criqui, M.H.; Greenland, P.; Guralnik, J.M.; Chan, C.; Schneider, J.R.; Mandapat, A.L.; Martin, G.; McDermott, M.M. Peripheral artery disease, diabetes, and reduced lower extremity functioning. Diabetes Care 2002, 25, 113–120. [Google Scholar] [CrossRef] [PubMed]
  27. Prompers, L.; Schaper, N.; Apelqvist, J.; Edmonds, M.; Jude, E.; Mauricio, D.; Uccioli, L.; Urbancic, V.; Bakker, K.; Holstein, P.; et al. Prediction of outcome in individuals with diabetic foot ulcers: Focus on the differences between individuals with and without peripheral arterial disease. The EURODIALE Study. Diabetologia 2008, 51, 747–755. [Google Scholar] [CrossRef] [PubMed]
  28. Ruiter, M.S.; van Golde, J.M.; Schaper, N.C.; Stehouwer, C.D.; Huijberts, M.S. Diabetes impairs arteriogenesis in the peripheral circulation: Review of molecular mechanisms. Clin. Sci. (Lond.) 2010, 119, 225–238. [Google Scholar] [CrossRef] [PubMed]
  29. Ziegler-Graham, K.; MacKenzie, E.J.; Ephraim, P.L.; Travison, T.G.; Brookmeyer, R. Estimating the prevalence of limb loss in the United States: 2005 to 2050. Arch. Phys. Med. Rehabil. 2008, 89, 422–429. [Google Scholar] [CrossRef] [PubMed]
  30. Faglia, E.; Clerici, G.; Clerissi, J.; Gabrielli, L.; Losa, S.; Mantero, M.; Caminiti, M.; Curci, V.; Quarantiello, A.; Lupattelli, T.; et al. Long-term prognosis of diabetic patients with critical limb ischemia: A population-based cohort study. Diabetes Care 2009, 32, 822–827. [Google Scholar] [CrossRef] [PubMed]
  31. Santulli, G.; Lombardi, A.; Sorriento, D.; Anastasio, A.; Del Giudice, C.; Formisano, P.; Beguinot, F.; Trimarco, B.; Miele, C.; Iaccarino, G. Age-related impairment in insulin release: The essential role of beta(2)-adrenergic receptor. Diabetes 2012, 61, 692–701. [Google Scholar] [CrossRef] [PubMed][Green Version]
  32. Rosengren, A.H.; Jokubka, R.; Tojjar, D.; Granhall, C.; Hansson, O.; Li, D.Q.; Nagaraj, V.; Reinbothe, T.M.; Tuncel, J.; Eliasson, L.; et al. Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes. Science 2010, 327, 217–220. [Google Scholar] [CrossRef] [PubMed]
  33. Nevzorova, J.; Evans, B.A.; Bengtsson, T.; Summers, R.J. Multiple signalling pathways involved in beta2-adrenoceptor-mediated glucose uptake in rat skeletal muscle cells. Br. J. Pharmacol. 2006, 147, 446–454. [Google Scholar] [CrossRef] [PubMed]
  34. Hutchinson, D.S.; Bengtsson, T. alpha1A-adrenoceptors activate glucose uptake in L6 muscle cells through a phospholipase C-phosphatidylinositol-3 kinase-, and atypical protein kinase C.-dependent pathway. Endocrinology 2005, 146, 901–912. [Google Scholar] [CrossRef] [PubMed]
  35. Lembo, G.; Capaldo, B.; Rendina, V.; Iaccarino, G.; Napoli, R.; Guida, R.; Trimarco, B.; Sacca, L. Acute noradrenergic activation induces insulin resistance in human skeletal muscle. Am. J. Physiol. 1994, 266, E242–E247. [Google Scholar] [CrossRef] [PubMed]
  36. Cipolletta, E.; Del Giudice, C.; Santulli, G.; Trimarco, B.; Iaccarino, G. Opposite effects of beta2-adrenoceptor gene deletion on insulin signaling in liver and skeletal muscle. Nutr. Metab. Cardiovasc. Dis. 2017, 27, 615–623. [Google Scholar] [CrossRef] [PubMed]
  37. Basu, R.; Breda, E.; Oberg, A.L.; Powell, C.C.; Dalla Man, C.; Basu, A.; Vittone, J.L.; Klee, G.G.; Arora, P.; Jensen, M.D.; et al. Mechanisms of the age-associated deterioration in glucose tolerance: Contribution of alterations in insulin secretion, action, and clearance. Diabetes 2003, 52, 1738–1748. [Google Scholar] [CrossRef] [PubMed]
  38. Iozzo, P.; Beck-Nielsen, H.; Laakso, M.; Smith, U.; Yki-Jarvinen, H.; Ferrannini, E. Independent influence of age on basal insulin secretion in nondiabetic humans. European Group for the Study of Insulin Resistance. J. Clin. Endocrinol. Metab. 1999, 84, 863–868. [Google Scholar] [CrossRef] [PubMed]
  39. Ciccarelli, M.; Santulli, G.; Campanile, A.; Galasso, G.; Cervero, P.; Altobelli, G.G.; Cimini, V.; Pastore, L.; Piscione, F.; Trimarco, B.; et al. Endothelial alpha1-adrenoceptors regulate neo-angiogenesis. Br. J. Pharmacol. 2008, 153, 936–946. [Google Scholar] [CrossRef] [PubMed]
  40. Ciccarelli, M.; Sorriento, D.; Cipolletta, E.; Santulli, G.; Fusco, A.; Zhou, R.H.; Eckhart, A.D.; Peppel, K.; Koch, W.J.; Trimarco, B.; et al. Impaired neoangiogenesis in beta(2)-adrenoceptor gene-deficient mice: Restoration by intravascular human beta(2)-adrenoceptor gene transfer and role of NFkappaB and CREB transcription factors. Br. J. Pharmacol. 2011, 162, 712–721. [Google Scholar] [CrossRef] [PubMed]
  41. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017; Centers for Disease Control and Prevention, US Department of Health and Human Services: Atlanta, GA, USA, 2017.
  42. Grant, P.J. Diabetes mellitus as a prothrombotic condition. J. Intern. Med. 2007, 262, 157–172. [Google Scholar] [CrossRef] [PubMed][Green Version]
  43. Blonde, L.; Klein, E.J.; Han, J.; Zhang, B.; Mac, S.M.; Poon, T.H.; Taylor, K.L.; Trautmann, M.E.; Kim, D.D.; Kendall, D.M. Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. Diabetes Obes. Metab. 2006, 8, 436–447. [Google Scholar] [CrossRef] [PubMed][Green Version]
  44. Chehade, J.M.; Alcalde, R.; Naem, E.; Mooradian, A.D.; Wong, N.C.; Haas, M.J. Induction of apolipoprotein A-I gene expression by glucagon-like peptide-1 and exendin-4 in hepatocytes but not intestinal cells. Metabolism 2013, 62, 265–274. [Google Scholar] [CrossRef] [PubMed]
  45. Irwin, N.; McClean, P.L.; Hunter, K.; Flatt, P.R. Metabolic effects of sustained activation of the GLP-1 receptor alone and in combination with background GIP receptor antagonism in high fat-fed mice. Diabetes Obes. Metab. 2009, 11, 603–610. [Google Scholar] [CrossRef] [PubMed]
  46. Parlevliet, E.T.; Schroder-van der Elst, J.P.; Corssmit, E.P.; Picha, K.; O’Neil, K.; Stojanovic-Susulic, V.; Ort, T.; Havekes, L.M.; Romijn, J.A.; Pijl, H. CNTO736, a novel glucagon-like peptide-1 receptor agonist, ameliorates insulin resistance and inhibits very low-density lipoprotein production in high-fat-fed mice. J. Pharmacol. Exp. Ther. 2009, 328, 240–248. [Google Scholar] [CrossRef] [PubMed]
  47. Qin, X.; Shen, H.; Liu, M.; Yang, Q.; Zheng, S.; Sabo, M.; D’Alessio, D.A.; Tso, P. GLP-1 reduces intestinal lymph flow, triglyceride absorption, and apolipoprotein production in rats. Am. J. Physiol. Gastrointest. Liver Physiol. 2005, 288, G943–G949. [Google Scholar] [CrossRef] [PubMed][Green Version]
  48. Vanderweele, D.A.; Geiselman, P.J.; Novin, D. Pancreatic glucagon, food deprivation and feeding in intact and vagotomized rabbits. Physiol. Behav. 1979, 23, 155–158. [Google Scholar] [CrossRef]
  49. Drucker, D.J.; Nauck, M.A. The incretin system: Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006, 368, 1696–1705. [Google Scholar] [CrossRef]
  50. Kirino, Y.; Sei, M.; Kawazoe, K.; Minakuchi, K.; Sato, Y. Plasma dipeptidyl peptidase 4 activity correlates with body mass index and the plasma adiponectin concentration in healthy young people. Endocr. J. 2012, 59, 949–953. [Google Scholar] [CrossRef] [PubMed][Green Version]
  51. Lamers, D.; Famulla, S.; Wronkowitz, N.; Hartwig, S.; Lehr, S.; Ouwens, D.M.; Eckardt, K.; Kaufman, J.M.; Ryden, M.; Muller, S.; et al. Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes 2011, 60, 1917–1925. [Google Scholar] [CrossRef] [PubMed]
  52. Gupta, N.A.; Mells, J.; Dunham, R.M.; Grakoui, A.; Handy, J.; Saxena, N.K.; Anania, F.A. Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology 2010, 51, 1584–1592. [Google Scholar] [CrossRef] [PubMed][Green Version]
  53. Bullock, B.P.; Heller, R.S.; Habener, J.F. Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. Endocrinology 1996, 137, 2968–2978. [Google Scholar] [CrossRef] [PubMed]
  54. D’Alessio, D.A.; Kahn, S.E.; Leusner, C.R.; Ensinck, J.W. Glucagon-like peptide 1 enhances glucose tolerance both by stimulation of insulin release and by increasing insulin-independent glucose disposal. J. Clin. Investig. 1994, 93, 2263–2266. [Google Scholar] [CrossRef] [PubMed]
  55. Seghieri, M.; Rebelos, E.; Gastaldelli, A.; Astiarraga, B.D.; Casolaro, A.; Barsotti, E.; Pocai, A.; Nauck, M.; Muscelli, E.; Ferrannini, E. Direct effect of GLP-1 infusion on endogenous glucose production in humans. Diabetologia 2013, 56, 156–161. [Google Scholar] [CrossRef] [PubMed]
  56. Iltz, J.L.; Baker, D.E.; Setter, S.M.; Keith Campbell, R. Exenatide: An incretin mimetic for the treatment of type 2 diabetes mellitus. Clin. Ther. 2006, 28, 652–665. [Google Scholar] [CrossRef] [PubMed]
  57. Eng, J.; Kleinman, W.A.; Singh, L.; Singh, G.; Raufman, J.P. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J. Biol. Chem. 1992, 267, 7402–7405. [Google Scholar] [PubMed]
  58. Dhanesha, N.; Joharapurkar, A.; Shah, G.; Dhote, V.; Kshirsagar, S.; Bahekar, R.; Jain, M. Exendin-4 reduces glycemia by increasing liver glucokinase activity: An insulin independent effect. Pharmacol. Rep. 2012, 64, 140–149. [Google Scholar] [CrossRef]
  59. Kolterman, O.G.; Buse, J.B.; Fineman, M.S.; Gaines, E.; Heintz, S.; Bicsak, T.A.; Taylor, K.; Kim, D.; Aisporna, M.; Wang, Y.; et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J. Clin. Endocrinol. Metab. 2003, 88, 3082–3089. [Google Scholar] [CrossRef] [PubMed]
  60. Degn, K.B.; Brock, B.; Juhl, C.B.; Djurhuus, C.B.; Grubert, J.; Kim, D.; Han, J.; Taylor, K.; Fineman, M.; Schmitz, O. Effect of intravenous infusion of exenatide (synthetic exendin-4) on glucose-dependent insulin secretion and counterregulation during hypoglycemia. Diabetes 2004, 53, 2397–2403. [Google Scholar] [CrossRef] [PubMed]
  61. Gedulin, B.R.; Nikoulina, S.E.; Smith, P.A.; Gedulin, G.; Nielsen, L.L.; Baron, A.D.; Parkes, D.G.; Young, A.A. Exenatide (exendin-4) improves insulin sensitivity and {beta}-cell mass in insulin-resistant obese fa/fa Zucker rats independent of glycemia and body weight. Endocrinology 2005, 146, 2069–2076. [Google Scholar] [CrossRef] [PubMed]
  62. Guo, C.; Huang, T.; Chen, A.; Chen, X.; Wang, L.; Shen, F.; Gu, X. Glucagon-like peptide 1 improves insulin resistance in vitro through anti-inflammation of macrophages. Braz. J. Med. Biol. Res. 2016, 49, e5826. [Google Scholar] [CrossRef] [PubMed]
  63. Idris, I.; Patiag, D.; Gray, S.; Donnelly, R. Exendin-4 increases insulin sensitivity via a PI-3-kinase-dependent mechanism: Contrasting effects of GLP-1. Biochem. Pharmacol. 2002, 63, 993–996. [Google Scholar] [CrossRef]
  64. Wang, A.; Li, T.; An, P.; Yan, W.; Zheng, H.; Wang, B.; Mu, Y. Exendin-4 Upregulates Adiponectin Level in Adipocytes via Sirt1/Foxo-1 Signaling Pathway. PLoS ONE 2017, 12, e0169469. [Google Scholar] [CrossRef] [PubMed]
  65. Ban, K.; Noyan-Ashraf, M.H.; Hoefer, J.; Bolz, S.S.; Drucker, D.J.; Husain, M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation 2008, 117, 2340–2350. [Google Scholar] [CrossRef] [PubMed]
  66. Du, X.L.; Edelstein, D.; Dimmeler, S.; Ju, Q.; Sui, C.; Brownlee, M. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J. Clin. Investig. 2001, 108, 1341–1348. [Google Scholar] [CrossRef] [PubMed][Green Version]
  67. Guzik, T.J.; Mussa, S.; Gastaldi, D.; Sadowski, J.; Ratnatunga, C.; Pillai, R.; Channon, K.M. Mechanisms of increased vascular superoxide production in human diabetes mellitus: Role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation 2002, 105, 1656–1662. [Google Scholar] [CrossRef] [PubMed]
  68. Wenzel, P.; Daiber, A.; Oelze, M.; Brandt, M.; Closs, E.; Xu, J.; Thum, T.; Bauersachs, J.; Ertl, G.; Zou, M.H.; et al. Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus. Atherosclerosis 2008, 198, 65–76. [Google Scholar] [CrossRef] [PubMed][Green Version]
  69. Shah, Z.; Pineda, C.; Kampfrath, T.; Maiseyeu, A.; Ying, Z.; Racoma, I.; Deiuliis, J.; Xu, X.; Sun, Q.; Moffatt-Bruce, S.; et al. Acute DPP-4 inhibition modulates vascular tone through GLP-1 independent pathways. Vasc. Pharmacol. 2011, 55, 2–9. [Google Scholar] [CrossRef] [PubMed][Green Version]
  70. Qi, S.Y.; Riviere, P.J.; Trojnar, J.; Junien, J.L.; Akinsanya, K.O. Cloning and characterization of dipeptidyl peptidase 10, a new member of an emerging subgroup of serine proteases. Biochem. J. 2003, 373, 179–189. [Google Scholar] [CrossRef] [PubMed]
  71. Polgar, L. The prolyl oligopeptidase family. Cell. Mol. Life Sci. 2002, 59, 349–362. [Google Scholar] [CrossRef] [PubMed]
  72. Rawlings, N.D.; Polgar, L.; Barrett, A.J. A new family of serine-type peptidases related to prolyl oligopeptidase. Biochem. J. 1991, 279 Pt 3, 907–908. [Google Scholar] [CrossRef]
  73. Sedo, A.; Malik, R. Dipeptidyl peptidase IV-like molecules: Homologous proteins or homologous activities? Biochim. Biophys. Acta 2001, 1550, 107–116. [Google Scholar] [CrossRef]
  74. Niedermeyer, J.; Enenkel, B.; Park, J.E.; Lenter, M.; Rettig, W.J.; Damm, K.; Schnapp, A. Mouse fibroblast-activation protein—Conserved Fap gene organization and biochemical function as a serine protease. Eur. J. Biochem. 1998, 254, 650–654. [Google Scholar] [CrossRef] [PubMed]
  75. Jacotot, E.; Callebaut, C.; Blanco, J.; Krust, B.; Neubert, K.; Barth, A.; Hovanessian, A.G. Dipeptidyl-peptidase IV-beta, a novel form of cell-surface-expressed protein with dipeptidyl-peptidase IV activity. Eur. J. Biochem. 1996, 239, 248–258. [Google Scholar] [CrossRef] [PubMed]
  76. Wada, K.; Yokotani, N.; Hunter, C.; Doi, K.; Wenthold, R.J.; Shimasaki, S. Differential expression of two distinct forms of mRNA encoding members of a dipeptidyl aminopeptidase family. Proc. Natl. Acad. Sci. USA 1992, 89, 197–201. [Google Scholar] [CrossRef] [PubMed]
  77. Fukasawa, K.M.; Fukasawa, K.; Higaki, K.; Shiina, N.; Ohno, M.; Ito, S.; Otogoto, J.; Ota, N. Cloning and functional expression of rat kidney dipeptidyl peptidase II. Biochem. J. 2001, 353, 283–290. [Google Scholar] [CrossRef] [PubMed]
  78. Abbott, C.A.; Yu, D.M.; Woollatt, E.; Sutherland, G.R.; McCaughan, G.W.; Gorrell, M.D. Cloning, expression and chromosomal localization of a novel human dipeptidyl peptidase (DPP) IV homolog, DPP8. Eur. J. Biochem. 2000, 267, 6140–6150. [Google Scholar] [CrossRef] [PubMed][Green Version]
  79. Wang, Z.; Grigo, C.; Steinbeck, J.; von Horsten, S.; Amann, K.; Daniel, C. Soluble DPP4 originates in part from bone marrow cells and not from the kidney. Peptides 2014, 57, 109–117. [Google Scholar] [CrossRef] [PubMed]
  80. Mentlein, R. Dipeptidyl-peptidase IV (CD26)—Role in the inactivation of regulatory peptides. Regul. Pept. 1999, 85, 9–24. [Google Scholar] [CrossRef]
  81. Zhong, J.; Rao, X.; Deiuliis, J.; Braunstein, Z.; Narula, V.; Hazey, J.; Mikami, D.; Needleman, B.; Satoskar, A.R.; Rajagopalan, S. A potential role for dendritic cell/macrophage-expressing DPP4 in obesity-induced visceral inflammation. Diabetes 2013, 62, 149–157. [Google Scholar] [CrossRef] [PubMed]
  82. Morimoto, C.; Schlossman, S.F. The structure and function of CD26 in the T-cell immune response. Immunol. Rev. 1998, 161, 55–70. [Google Scholar] [CrossRef] [PubMed]
  83. Shah, Z.; Kampfrath, T.; Deiuliis, J.A.; Zhong, J.; Pineda, C.; Ying, Z.; Xu, X.; Lu, B.; Moffatt-Bruce, S.; Durairaj, R.; et al. Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation 2011, 124, 2338–2349. [Google Scholar] [CrossRef] [PubMed]
  84. Sueyoshi, R.; Woods Ignatoski, K.M.; Okawada, M.; Hartmann, B.; Holst, J.; Teitelbaum, D.H. Stimulation of intestinal growth and function with DPP4 inhibition in a mouse short bowel syndrome model. Am. J. Physiol. Gastrointest. Liver Physiol. 2014, 307, G410–G419. [Google Scholar] [CrossRef] [PubMed]
  85. Ben-Shlomo, S.; Zvibel, I.; Shnell, M.; Shlomai, A.; Chepurko, E.; Halpern, Z.; Barzilai, N.; Oren, R.; Fishman, S. Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase. J. Hepatol. 2011, 54, 1214–1223. [Google Scholar] [CrossRef] [PubMed]
  86. Richard, E.; Arredondo-Vega, F.X.; Santisteban, I.; Kelly, S.J.; Patel, D.D.; Hershfield, M.S. The binding site of human adenosine deaminase for CD26/Dipeptidyl peptidase IV: The Arg142Gln mutation impairs binding to cd26 but does not cause immune deficiency. J. Exp. Med. 2000, 192, 1223–1236. [Google Scholar] [CrossRef] [PubMed]
  87. Masur, K.; Schwartz, F.; Entschladen, F.; Niggemann, B.; Zaenker, K.S. DPPIV inhibitors extend GLP-2 mediated tumour promoting effects on intestinal cancer cells. Regul. Pept. 2006, 137, 147–155. [Google Scholar] [CrossRef] [PubMed]
  88. Ahren, B.; Hughes, T.E. Inhibition of dipeptidyl peptidase-4 augments insulin secretion in response to exogenously administered glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, pituitary adenylate cyclase-activating polypeptide, and gastrin-releasing peptide in mice. Endocrinology 2005, 146, 2055–2059. [Google Scholar] [CrossRef] [PubMed]
  89. Zhong, J.; Rao, X.; Rajagopalan, S. An emerging role of dipeptidyl peptidase 4 (DPP4) beyond glucose control: Potential implications in cardiovascular disease. Atherosclerosis 2013, 226, 305–314. [Google Scholar] [CrossRef] [PubMed]
  90. Devin, J.K.; Pretorius, M.; Nian, H.; Yu, C.; Billings FTt and Brown, N.J. Dipeptidyl-peptidase 4 inhibition and the vascular effects of glucagon-like peptide-1 and brain natriuretic peptide in the human forearm. J. Am. Heart. Assoc. 2014, 3. [Google Scholar] [CrossRef] [PubMed]
  91. Busek, P.; Stremenova, J.; Krepela, E.; Sedo, A. Modulation of substance P signaling by dipeptidyl peptidase-IV enzymatic activity in human glioma cell lines. Physiol. Res. 2008, 57, 443–449. [Google Scholar] [PubMed]
  92. Reinehr, T.; Roth, C.L.; Enriori, P.J.; Masur, K. Changes of dipeptidyl peptidase IV (DPP-IV) in obese children with weight loss: Relationships to peptide, Y.Y.; pancreatic peptide, and insulin sensitivity. J. Pediatr. Endocrinol. Metab. 2010, 23, 101–108. [Google Scholar] [CrossRef] [PubMed]
  93. Wagner, L.; Kaestner, F.; Wolf, R.; Stiller, H.; Heiser, U.; Manhart, S.; Hoffmann, T.; Rahfeld, J.U.; Demuth, H.U.; Rothermundt, M.; et al. Identifying neuropeptide Y (NPY) as the main stress-related substrate of dipeptidyl peptidase 4 (DPP4) in blood circulation. Neuropeptides 2016, 57, 21–34. [Google Scholar] [CrossRef] [PubMed]
  94. Ajami, K.; Pitman, M.R.; Wilson, C.H.; Park, J.; Menz, R.I.; Starr, A.E.; Cox, J.H.; Abbott, C.A.; Overall, C.M.; Gorrell, M.D. Stromal cell-derived factors 1alpha and 1beta, inflammatory protein-10 and interferon-inducible T cell chemo-attractant are novel substrates of dipeptidyl peptidase 8. FEBS Lett. 2008, 582, 819–825. [Google Scholar] [CrossRef] [PubMed]
  95. Nieto-Fontarigo, J.J.; Gonzalez-Barcala, F.J.; San-Jose, M.E.; Cruz, M.J.; Linares, T.; Soto-Mera, M.T.; Valdes-Cuadrado, L.; Garcia-Gonzalez, M.A.; Andrade-Bulos, L.J.; Arias, P.; et al. Expansion of a CD26low Effector TH Subset and Reduction in Circulating Levels of sCD26 in Stable Allergic Asthma in Adults. J. Investig. Allergol. Clin. Immunol. 2018, 28, 113–125. [Google Scholar] [CrossRef] [PubMed]
  96. Proost, P.; Schutyser, E.; Menten, P.; Struyf, S.; Wuyts, A.; Opdenakker, G.; Detheux, M.; Parmentier, M.; Durinx, C.; Lambeir, A.M.; et al. Amino-terminal truncation of CXCR3 agonists impairs receptor signaling and lymphocyte chemotaxis, while preserving antiangiogenic properties. Blood 2001, 98, 3554–3561. [Google Scholar] [CrossRef] [PubMed][Green Version]
  97. Mulvihill, E.E.; Drucker, D.J. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr. Rev. 2014, 35, 992–1019. [Google Scholar] [CrossRef] [PubMed]
  98. Iwata, S.; Yamaguchi, N.; Munakata, Y.; Ikushima, H.; Lee, J.F.; Hosono, O.; Schlossman, S.F.; Morimoto, C. CD26/dipeptidyl peptidase IV differentially regulates the chemotaxis of T cells and monocytes toward RANTES: Possible mechanism for the switch from innate to acquired immune response. Int. Immunol. 1999, 11, 417–426. [Google Scholar] [CrossRef] [PubMed]
  99. Broxmeyer, H.E.; Hoggatt, J.; O’Leary, H.A.; Mantel, C.; Chitteti, B.R.; Cooper, S.; Messina-Graham, S.; Hangoc, G.; Farag, S.; Rohrabaugh, S.L.; et al. Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis. Nat. Med. 2012, 18, 1786–1796. [Google Scholar] [CrossRef] [PubMed][Green Version]
  100. Pacheco, R.; Martinez-Navio, J.M.; Lejeune, M.; Climent, N.; Oliva, H.; Gatell, J.M.; Gallart, T.; Mallol, J.; Lluis, C.; Franco, R. CD26, adenosine deaminase, and adenosine receptors mediate costimulatory signals in the immunological synapse. Proc. Natl. Acad. Sci. USA 2005, 102, 9583–9588. [Google Scholar] [CrossRef] [PubMed][Green Version]
  101. Ohnuma, K.; Uchiyama, M.; Yamochi, T.; Nishibashi, K.; Hosono, O.; Takahashi, N.; Kina, S.; Tanaka, H.; Lin, X.; Dang, N.H.; et al. Caveolin-1 triggers T-cell activation via CD26 in association with CARMA1. J. Biol. Chem. 2007, 282, 10117–10131. [Google Scholar] [CrossRef] [PubMed]
  102. Ikushima, H.; Munakata, Y.; Ishii, T.; Iwata, S.; Terashima, M.; Tanaka, H.; Schlossman, S.F.; Morimoto, C. Internalization of CD26 by mannose 6-phosphate/insulin-like growth factor II receptor contributes to T. cell activation. Proc. Natl. Acad. Sci. USA 2000, 97, 8439–8444. [Google Scholar] [CrossRef] [PubMed]
  103. Salgado, F.J.; Lojo, J.; Alonso-Lebrero, J.L.; Lluis, C.; Franco, R.; Cordero, O.J.; Nogueira, M. A role for interleukin-12 in the regulation of T cell plasma membrane compartmentation. J. Biol. Chem. 2003, 278, 24849–24857. [Google Scholar] [CrossRef] [PubMed]
  104. Ghersi, G.; Zhao, Q.; Salamone, M.; Yeh, Y.; Zucker, S.; Chen, W.T. The protease complex consisting of dipeptidyl peptidase, I.V.; seprase plays a role in the migration and invasion of human endothelial cells in collagenous matrices. Cancer Res. 2006, 66, 4652–4661. [Google Scholar] [CrossRef] [PubMed]
  105. Ohnuma, K.; Yamochi, T.; Uchiyama, M.; Nishibashi, K.; Yoshikawa, N.; Shimizu, N.; Iwata, S.; Tanaka, H.; Dang, N.H.; Morimoto, C. CD26 up-regulates expression of CD86 on antigen-presenting cells by means of caveolin-1. Proc. Natl. Acad. Sci. USA 2004, 101, 14186–14191. [Google Scholar] [CrossRef] [PubMed][Green Version]
  106. Girardi, A.C.; Degray, B.C.; Nagy, T.; Biemesderfer, D.; Aronson, P.S. Association of Na(+)-H(+) exchanger isoform NHE3 and dipeptidyl peptidase IV in the renal proximal tubule. J. Biol. Chem. 2001, 276, 46671–46677. [Google Scholar] [CrossRef] [PubMed]
  107. Weihofen, W.A.; Liu, J.; Reutter, W.; Saenger, W.; Fan, H. Crystal structures of HIV-1 Tat-derived nonapeptides Tat-(1-9) and Trp2-Tat-(1-9) bound to the active site of dipeptidyl-peptidase IV (CD26). J. Biol. Chem. 2005, 280, 14911–14917. [Google Scholar] [CrossRef] [PubMed]
  108. Askari, A.T.; Unzek, S.; Popovic, Z.B.; Goldman, C.K.; Forudi, F.; Kiedrowski, M.; Rovner, A.; Ellis, S.G.; Thomas, J.D.; DiCorleto, P.E.; et al. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 2003, 362, 697–703. [Google Scholar] [CrossRef]
  109. Deglurkar, I.; Mal, N.; Mills, W.R.; Popovic, Z.B.; McCarthy, P.; Blackstone, E.H.; Laurita, K.R.; Penn, M.S. Mechanical and electrical effects of cell-based gene therapy for ischemic cardiomyopathy are independent. Hum. Gene Ther. 2006, 17, 1144–1151. [Google Scholar] [CrossRef] [PubMed]
  110. Sundararaman, S.; Miller, T.J.; Pastore, J.M.; Kiedrowski, M.; Aras, R.; Penn, M.S. Plasmid-based transient human stromal cell-derived factor-1 gene transfer improves cardiac function in chronic heart failure. Gene Ther. 2011, 18, 867–873. [Google Scholar] [CrossRef] [PubMed]
  111. Zhang, M.; Mal, N.; Kiedrowski, M.; Chacko, M.; Askari, A.T.; Popovic, Z.B.; Koc, O.N.; Penn, M.S. SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction. FASEB J. 2007, 21, 3197–3207. [Google Scholar] [CrossRef] [PubMed][Green Version]
  112. Christopherson, K.W.; Hangoc, G.; Mantel, C.R.; Broxmeyer, H.E. Modulation of hematopoietic stem cell homing and engraftment by CD26. Science 2004, 305, 1000–1003. [Google Scholar] [CrossRef] [PubMed]
  113. Zaruba, M.M.; Theiss, H.D.; Vallaster, M.; Mehl, U.; Brunner, S.; David, R.; Fischer, R.; Krieg, L.; Hirsch, E.; Huber, B.; et al. Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell 2009, 4, 313–323. [Google Scholar] [CrossRef] [PubMed]
  114. Dingenouts, C.K.E.; Bakker, W.; Lodder, K.; Wiesmeijer, K.C.; Moerkamp, A.T.; Maring, J.A.; Arthur, H.M.; Smits, A.M.; Goumans, M.J. Inhibiting DPP4 in a mouse model of HHT1 results in a shift towards regenerative macrophages and reduces fibrosis after myocardial infarction. PLoS ONE 2017, 12, e0189805. [Google Scholar] [CrossRef] [PubMed]
  115. Haverslag, R.T.; de Groot, D.; Grundmann, S.; Meder, B.; Goumans, M.J.; Pasterkamp, G.; Hoefer, I.E.; de Kleijn, D.P. CD26 inhibition enhances perfusion recovery in ApoE-/-mice. Curr. Vasc. Pharmacol. 2013, 11, 21–28. [Google Scholar] [CrossRef] [PubMed]
  116. Peled, A.; Kollet, O.; Ponomaryov, T.; Petit, I.; Franitza, S.; Grabovsky, V.; Slav, M.M.; Nagler, A.; Lider, O.; Alon, R.; et al. The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34(+) cells: Role in transendothelial/stromal migration and engraftment of NOD/SCID mice. Blood 2000, 95, 3289–3296. [Google Scholar] [PubMed]
  117. Ganju, R.K.; Brubaker, S.A.; Meyer, J.; Dutt, P.; Yang, Y.; Qin, S.; Newman, W.; Groopman, J.E. The alpha-chemokine, stromal cell-derived factor-1alpha, binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways. J. Biol. Chem. 1998, 273, 23169–23175. [Google Scholar] [CrossRef] [PubMed]
  118. Thomas, M.N.; Kalnins, A.; Andrassy, M.; Wagner, A.; Klussmann, S.; Rentsch, M.; Habicht, A.; Pratschke, S.; Stangl, M.; Bazhin, A.V.; et al. SDF-1/CXCR4/CXCR7 is pivotal for vascular smooth muscle cell proliferation and chronic allograft vasculopathy. Transpl. Int. 2015, 28, 1426–1435. [Google Scholar] [CrossRef] [PubMed][Green Version]
  119. De Groot, D.; Haverslag, R.T.; Pasterkamp, G.; de Kleijn, D.P.; Hoefer, I.E. Targeted deletion of the inhibitory NF-kappaB p50 subunit in bone marrow-derived cells improves collateral growth after arterial occlusion. Cardiovasc. Res. 2010, 88, 179–185. [Google Scholar] [CrossRef] [PubMed]
  120. Eitenmuller, I.; Volger, O.; Kluge, A.; Troidl, K.; Barancik, M.; Cai, W.J.; Heil, M.; Pipp, F.; Fischer, S.; Horrevoets, A.J.; et al. The range of adaptation by collateral vessels after femoral artery occlusion. Circ. Res. 2006, 99, 656–662. [Google Scholar] [CrossRef] [PubMed]
  121. Hoefer, I.E.; van Royen, N.; Rectenwald, J.E.; Bray, E.J.; Abouhamze, Z.; Moldawer, L.L.; Voskuil, M.; Piek, J.J.; Buschmann, I.R.; Ozaki, C.K. Direct evidence for tumor necrosis factor-alpha signaling in arteriogenesis. Circulation 2002, 105, 1639–1641. [Google Scholar] [CrossRef] [PubMed]
  122. Van Royen, N.; Hoefer, I.; Buschmann, I.; Heil, M.; Kostin, S.; Deindl, E.; Vogel, S.; Korff, T.; Augustin, H.; Bode, C.; et al. Exogenous application of transforming growth factor beta 1 stimulates arteriogenesis in the peripheral circulation. FASEB J. 2002. [Google Scholar] [CrossRef] [PubMed]
  123. Krieger, J.R.; Ogle, M.E.; McFaline-Figueroa, J.; Segar, C.E.; Temenoff, J.S.; Botchwey, E.A. Spatially localized recruitment of anti-inflammatory monocytes by SDF-1alpha-releasing hydrogels enhances microvascular network remodeling. Biomaterials 2015, 77, 280–290. [Google Scholar] [CrossRef] [PubMed]
  124. Troidl, C.; Jung, G.; Troidl, K.; Hoffmann, J.; Mollmann, H.; Nef, H.; Schaper, W.; Hamm, C.W.; Schmitz-Rixen, T. The temporal and spatial distribution of macrophage subpopulations during arteriogenesis. Curr. Vasc. Pharmacol. 2013, 11, 5–12. [Google Scholar] [CrossRef] [PubMed]
  125. Brenner, C.; Franz, W.M.; Kuhlenthal, S.; Kuschnerus, K.; Remm, F.; Gross, L.; Theiss, H.D.; Landmesser, U.; Krankel, N. DPP-4 inhibition ameliorates atherosclerosis by priming monocytes into M2 macrophages. Int. J. Cardiol. 2015, 199, 163–169. [Google Scholar] [CrossRef] [PubMed]
  126. Lee, Y.S.; Shin, S.; Shigihara, T.; Hahm, E.; Liu, M.J.; Han, J.; Yoon, J.W.; Jun, H.S. Glucagon-like peptide-1 gene therapy in obese diabetic mice results in long-term cure of diabetes by improving insulin sensitivity and reducing hepatic gluconeogenesis. Diabetes 2007, 56, 1671–1679. [Google Scholar] [CrossRef] [PubMed]
  127. Van Weel, V.; de Vries, M.; Voshol, P.J.; Verloop, R.E.; Eilers, P.H.; van Hinsbergh, V.W.; van Bockel, J.H.; Quax, P.H. Hypercholesterolemia reduces collateral artery growth more dominantly than hyperglycemia or insulin resistance in mice. Arterioscler. Thromb. Vasc. Biol. 2006, 26, 1383–1390. [Google Scholar] [CrossRef] [PubMed]
  128. Buschmann, I.R.; Hoefer, I.E.; van Royen, N.; Katzer, E.; Braun-Dulleaus, R.; Heil, M.; Kostin, S.; Bode, C.; Schaper, W. GM-CSF: A strong arteriogenic factor acting by amplification of monocyte function. Atherosclerosis 2001, 159, 343–356. [Google Scholar] [CrossRef]
  129. Deindl, E.; Zaruba, M.M.; Brunner, S.; Huber, B.; Mehl, U.; Assmann, G.; Hoefer, I.E.; Mueller-Hoecker, J.; Franz, W.M. G-CSF administration after myocardial infarction in mice attenuates late ischemic cardiomyopathy by enhanced arteriogenesis. FASEB J. 2006, 20, 956–958. [Google Scholar] [CrossRef] [PubMed]
  130. Meier, P.; Hemingway, H.; Lansky, A.J.; Knapp, G.; Pitt, B.; Seiler, C. The impact of the coronary collateral circulation on mortality: A meta-analysis. Eur. Heart. J. 2012, 33, 614–621. [Google Scholar] [CrossRef] [PubMed]
  131. Fazel, S.; Cimini, M.; Chen, L.; Li, S.; Angoulvant, D.; Fedak, P.; Verma, S.; Weisel, R.D.; Keating, A.; Li, R.K. Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines. J. Clin. Investig. 2006, 116, 1865–1877. [Google Scholar] [CrossRef] [PubMed][Green Version]
  132. Green, J.B.; Bethel, M.A.; Armstrong, P.W.; Buse, J.B.; Engel, S.S.; Garg, J.; Josse, R.; Kaufman, K.D.; Koglin, J.; Korn, S.; et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N. Engl. J. Med. 2015, 373, 232–242. [Google Scholar] [CrossRef] [PubMed]
  133. Scirica, B.M.; Bhatt, D.L.; Braunwald, E.; Steg, P.G.; Davidson, J.; Hirshberg, B.; Ohman, P.; Frederich, R.; Wiviott, S.D.; Hoffman, E.B.; et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N. Engl. J. Med. 2013, 369, 1317–1326. [Google Scholar] [CrossRef] [PubMed]
  134. Boucaud-Maitre, D. Inclusion of the EXAMINE study in a meta-analysis of the addition of dipeptidyl peptidase-4 inhibitors to sulphonylureas and risk of hypoglycaemia. BMJ 2016, 353, i3186. [Google Scholar] [CrossRef] [PubMed]
  135. Scheen, A.J. Cardiovascular Effects of New Oral Glucose-Lowering Agents: DPP-4 and SGLT-2 Inhibitors. Circ. Res. 2018, 122, 1439–1459. [Google Scholar] [CrossRef] [PubMed]
  136. Rosenstock, J.; Marx, N.; Kahn, S.E.; Zinman, B.; Kastelein, J.J.; Lachin, J.M.; Bluhmki, E.; Patel, S.; Johansen, O.E.; Woerle, H.J. Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: Rationale for the active-comparator CAROLINA trial. Diabetes Vasc. Dis. Res. 2013, 10, 289–301. [Google Scholar] [CrossRef] [PubMed][Green Version]
  137. Costa, P.Z.; Soares, R. Neovascularization in diabetes and its complications. Unraveling the angiogenic paradox. Life Sci. 2013, 92, 1037–1045. [Google Scholar] [CrossRef] [PubMed]
  138. Jawa, A.; Kcomt, J.; Fonseca, V.A. Diabetic nephropathy and retinopathy. Med. Clin. North Am. 2004, 88, 1001–1036. [Google Scholar] [CrossRef] [PubMed]
  139. Rao Kondapally Seshasai, S.; Kaptoge, S.; Thompson, A.; Di Angelantonio, E.; Gao, P.; Sarwar, N.; Whincup, P.H.; Mukamal, K.J.; Gillum, R.F.; Holme, I.; et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N. Engl. J. Med. 2011, 364, 829–841. [Google Scholar] [CrossRef] [PubMed][Green Version]
  140. Chao, C.T.; Wang, J.; Wu, H.Y.; Chien, K.L.; Hung, K.Y. Dipeptidyl peptidase 4 inhibitor use is associated with a lower risk of incident acute kidney injury in patients with diabetes. Oncotarget 2017, 8, 53028–53040. [Google Scholar] [CrossRef] [PubMed][Green Version]
  141. Chung, Y.R.; Park, S.W.; Kim, J.W.; Kim, J.H.; Lee, K. Protective Effects of Dipeptidyl Peptidase-4 Inhibitors on Progression of Diabetic Retinopathy in Patients with Type 2 Diabetes. Retina 2016, 36, 2357–2363. [Google Scholar] [CrossRef] [PubMed]
  142. Goncalves, A.; Almeida, L.; Silva, A.P.; Fontes-Ribeiro, C.; Ambrosio, A.F.; Cristovao, A.; Fernandes, R. The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin ameliorates retinal endothelial cell dysfunction triggered by inflammation. Biomed. Pharmacother. 2018, 102, 833–838. [Google Scholar] [CrossRef] [PubMed]
  143. Kanozawa, K.; Noguchi, Y.; Sugahara, S.; Nakamura, S.; Yamamoto, H.; Kaneko, K.; Kono, R.; Sato, S.; Ogawa, T.; Hasegawa, H.; et al. The renoprotective effect and safety of a DPP-4 inhibitor, sitagliptin, at a small dose in type 2 diabetic patients with a renal dysfunction when changed from other DPP-4 inhibitors: REAL trial. Clin. Exp. Nephrol. 2018, 22, 825–834. [Google Scholar] [CrossRef] [PubMed]
  144. Li, H.; Wang, Y.S. An angiotensin-converting enzyme inhibitor modulates stromal-derived factor-1 through CD26/dipeptidyl peptidase IV to inhibit laser-induced choroidal neovascularization. Mol. Vis. 2013, 19, 1107–1121. [Google Scholar] [PubMed]
  145. Theiss, H.D.; Gross, L.; Vallaster, M.; David, R.; Brunner, S.; Brenner, C.; Nathan, P.; Assmann, G.; Mueller-Hoecker, J.; Vogeser, M.; et al. Antidiabetic gliptins in combination with G-CSF enhances myocardial function and survival after acute myocardial infarction. Int. J. Cardiol. 2013, 168, 3359–3369. [Google Scholar] [CrossRef] [PubMed]
  146. Remm, F.; Krankel, N.; Lener, D.; Drucker, D.J.; Sopper, S.; Brenner, C. Sitagliptin Accelerates Endothelial Regeneration after Vascular Injury Independent from GLP1 Receptor Signaling. Stem Cells Int. 2018, 2018, 5284963. [Google Scholar] [CrossRef] [PubMed]
  147. Moraes, F.; Paye, J.; Mac Gabhann, F.; Zhuang, Z.W.; Zhang, J.; Lanahan, A.A.; Simons, M. Endothelial cell-dependent regulation of arteriogenesis. Circ. Res. 2013, 113, 1076–1086. [Google Scholar] [CrossRef] [PubMed]
  148. Ghorpade, D.S.; Ozcan, L.; Zheng, Z.; Nicoloro, S.M.; Shen, Y.; Chen, E.; Bluher, M.; Czech, M.P.; Tabas, I. Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance. Nature 2018, 555, 673–677. [Google Scholar] [CrossRef] [PubMed]
  149. Aschner, P.; Kipnes, M.S.; Lunceford, J.K.; Sanchez, M.; Mickel, C.; Williams-Herman, D.E. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 2006, 29, 2632–2637. [Google Scholar] [CrossRef] [PubMed]
  150. Jung, C.H.; Park, C.Y.; Ahn, K.J.; Kim, N.H.; Jang, H.C.; Lee, M.K.; Park, J.Y.; Chung, C.H.; Min, K.W.; Sung, Y.A.; et al. A randomized, double-blind, placebo-controlled, phase II clinical trial to investigate the efficacy and safety of oral DA-1229 in patients with type 2 diabetes mellitus who have inadequate glycaemic control with diet and exercise. Diabetes Metab. Res. Rev. 2015, 31, 295–306. [Google Scholar] [CrossRef] [PubMed]
  151. Kadowaki, T.; Kondo, K. Efficacy, safety and dose-response relationship of teneligliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus. Diabetes Obes. Metab. 2013, 15, 810–818. [Google Scholar] [CrossRef] [PubMed]
  152. Kutoh, E.; Ukai, Y. Alogliptin as an initial therapy in patients with newly diagnosed, drug naive type 2 diabetes: A randomized, control trial. Endocrine 2012, 41, 435–441. [Google Scholar] [CrossRef] [PubMed]
  153. Raz, I.; Hanefeld, M.; Xu, L.; Caria, C.; Williams-Herman, D.; Khatami, H. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia 2006, 49, 2564–2571. [Google Scholar] [CrossRef] [PubMed]
  154. Ristic, S.; Byiers, S.; Foley, J.; Holmes, D. Improved glycaemic control with dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes: Vildagliptin (LAF237) dose response. Diabetes Obes. Metab. 2005, 7, 692–698. [Google Scholar] [CrossRef] [PubMed]
  155. Syed, Y.Y.; McCormack, P.L. Exenatide Extended-Release: An Updated Review of Its Use in Type 2 Diabetes Mellitus. Drugs 2015, 75, 1141–1152. [Google Scholar] [CrossRef] [PubMed]
  156. Tan, X.; Cao, X.; Zhou, M.; Zou, P.; Hu, J. Efficacy and safety of once-weekly semaglutide for the treatment of type 2 diabetes. Expert Opin. Investig. Drugs 2017, 26, 1083–1089. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Arteriogenesis versus angiogenesis. The left picture displays a healthy human leg. In the left and the middle picture, a pre-existing collateral artery is shown. As arteries have the function to transport oxygenated blood to distal parts of the body—in the case of the femoral artery to the lower leg—occlusion of the femoral artery results in severe ischemic damage in the lower leg (middle picture). This is associated with extensive angiogenesis. However, the reason for capillary sprouting in this case is not to locally provide oxygen and metabolites—this is simply not possible as long as the feeding artery is occluded, or the bypassing pre-existing collateral has not yet been enlarged by growth—but to remove cell debris from tissue damaged by ischemia. The right picture shows a human leg with a completely occluded artery, which is bypassed by an effectively grown collateral artery compensating for the function of the occluded artery. Accordingly, there is minor ischemic damage in the lower leg with only little capillary sprouting. This picture reflects the tissue saving property of the process of arteriogenesis. Adapted from Chillo et al., 2016 [17] with the permission of Cell Reports.
Figure 1. Arteriogenesis versus angiogenesis. The left picture displays a healthy human leg. In the left and the middle picture, a pre-existing collateral artery is shown. As arteries have the function to transport oxygenated blood to distal parts of the body—in the case of the femoral artery to the lower leg—occlusion of the femoral artery results in severe ischemic damage in the lower leg (middle picture). This is associated with extensive angiogenesis. However, the reason for capillary sprouting in this case is not to locally provide oxygen and metabolites—this is simply not possible as long as the feeding artery is occluded, or the bypassing pre-existing collateral has not yet been enlarged by growth—but to remove cell debris from tissue damaged by ischemia. The right picture shows a human leg with a completely occluded artery, which is bypassed by an effectively grown collateral artery compensating for the function of the occluded artery. Accordingly, there is minor ischemic damage in the lower leg with only little capillary sprouting. This picture reflects the tissue saving property of the process of arteriogenesis. Adapted from Chillo et al., 2016 [17] with the permission of Cell Reports.
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Figure 2. Recruitment of bone marrow derived cells by inhibition of dipeptidyl-peptidase 4 (DPP4). Stromal-cell-derived factor-1 (SDF-1) is cleaved by DPP4 (blue arrow) resulting in inactivation of the chemokine (red arrow). Blocking the enzymatic activity of DPP4 by specific (pharmacological) inhibitors preserves SDF-1. By binding to the receptor, CXC-motive-chemokine receptor 4 (CXCR-4), which is expressed on stem cells, leukocytes, and mast cells, SDF-1 locally recruits bone marrow derived cells, which in turn promote e.g. vessel growth (see Section 6.1).
Figure 2. Recruitment of bone marrow derived cells by inhibition of dipeptidyl-peptidase 4 (DPP4). Stromal-cell-derived factor-1 (SDF-1) is cleaved by DPP4 (blue arrow) resulting in inactivation of the chemokine (red arrow). Blocking the enzymatic activity of DPP4 by specific (pharmacological) inhibitors preserves SDF-1. By binding to the receptor, CXC-motive-chemokine receptor 4 (CXCR-4), which is expressed on stem cells, leukocytes, and mast cells, SDF-1 locally recruits bone marrow derived cells, which in turn promote e.g. vessel growth (see Section 6.1).
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Table 1. DPP4 activity.
Table 1. DPP4 activity.
FunctionProteinResult of DPP4 Cleavage
Regulatory peptidesGLP-1Inactivation
GLP-2Inactivation
GIP Inactivation
GRPInactivation
GHRFInactivation
NeuropeptidesBNPActivity reduced
Substance PInactivation
Peptide YYReceptor specificity
NPYReceptor specificity
ChemokinesITACInactivation
IP-10Inactivation
EotaxinInactivation
MIGAltered cell type specificity
MDCInactivation
RANTESInactivation
G-CSFInactivation
GM-CSFInactivation
Abbreviations: Glucagon-like peptide 1 (GLP-1); glucose-dependent insulinotropic peptide (GIP); glucagon-like peptide-2 (GLP-2); gastrin-releasing peptide (GRP); growth-hormone-releasing factor (GHRF); B-type natriuretic peptide (BNP); neuropeptide Y (NPY); interferon-inducible T cell α chemoattractant (ITAC); interferon-γ-induced protein-10 (IP-10); monokine induced by interferon γ (MIG); macrophage derived chemokine (MDC); regulated on activation normal T cell expressed and presumably secreted (RANTES); granulocyte colony stimulating factor (G-CSF); granulocyte monocyte colony stimulating factor (GM-CSF); stromal-cell-derived factor-1 (SDF-1).
Table 2. Meta-analyses of clinical trials using DPP4 inhibitors.
Table 2. Meta-analyses of clinical trials using DPP4 inhibitors.
StudyEndpoint
SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Type 2 Diabetes Mellitus [133]cardiovascular death, nonfatal myocardial infarction, nonfatal stroke
TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin [132]cardiovascular death, nonfatal myocardial infarction, nonfatal stroke
EXAMINE, Examination of Cardiovascular Outcomes: Alogliptin vs. Standard Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome [134]cardiovascular death, nonfatal myocardial infarction, nonfatal stroke
CAROLINA, Cardiovascular Outcome Study of Linagliptin v.s. Glimepride in Patients with Type 2 Diabetes Mellitus [136]cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, unstable angina pectoris
Reviewed 2018 by S. J. Scheen, see [135].

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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