glucagon-like-peptide-1 and Aortic-Aneurysm--Abdominal

Recent antidiabetic drugs including GLP-1 receptor agonists and DPP-IV inhibitors have demonstrated protective effects in several cardiovascular diseases but their effect in abdominal aortic aneurysm (AAA) is far less known. AAA can be associated with extremely high rates of mortality and pharmacological treatments are still lacking underlining the real need to identify new therapeutic targets. The aim of this review was to summarize current knowledge on the role of GLP-1 pathway in AAA. A systematic literature review was performed and 6 relevant studies (2 clinical and 4 experimental) were included. Experimental studies demonstrated a protective effect of both GLP-1 receptor agonists and DPP-IV inhibitors through targeting the main pathophysiological mechanisms underlying AAA formation. The effects of these drugs in human AAA are still poorly known. In the limelight of clinical and experimental studies, we discuss current limits and future directions.

Topics: Animals; Aortic Aneurysm, Abdominal; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans

Abdominal aortic aneurysms (AAAs) are characterized by the destruction of elastin and collagen in the media and adventitia. Dipeptidyl peptidase-4 (DPP-4, an adipokine known as CD26) influences cell signaling, cell-matrix interactions, and the regulation of the functional activity of incretins in metabolic and inflammatory disorders. Although the role of DPP-4 in AAA evolution has been demonstrated, the underlying mechanisms of DPP-4-regulated AAA development remains unknown.. Patients with AAA (n = 93) and healthy controls (CTL, n = 20) were recruited. Based on computed tomography image analyses, 93 patients were divided into two groups: those with a small AAA (SAA, aortic diameter <5 cm, n = 16) and those with a large AAA (LAA, aortic diameter ≥5 cm, n = 77). Plasma DPP-4, glucagon-like peptide-1 levels, and expression of CD26 on mononuclear cells were analyzed. In addition, phorbol 12-myristate 13-acetate (PMA)-induced THP-1 cells and angiotensin II-infused apolipoprotein E. The levels of DPP-4 (μU/μg) increased while active glucagon-like peptide-1 (pM) decreased in patients with AAA in a diameter-dependent manner [CTL: 2.3 ± 1.5 and 3.7 ± 2.4, respectively; SAA: 10.0 ± 10.9 and 2.1 ± 0.9, respectively; LAA: 32.2 ± 15.0 and 1.8 ± 1.1, respectively]. A significant decline in monocyte CD26 expression in patients with AAAs was observed relative to the CTL group. In vitro studies demonstrated that the inhibition of DPP-4 promoted PMA-induced monocytic cells differentiation, with increased CD68 and p21 expression, regulated by extracellular signal-regulated protein kinase 1/2 activation. Furthermore, inhibition of DPP-4 significantly increased the phosphorylation of PYK2 and paxillin in PMA-induced THP-1 cell differentiation. Finally, the animal study was used to confirm the in vitro results that LAA mice showed marked macrophage infiltration in the adventitia with a decreased expression of DPP-4 as compared with SAA mice.. Increased plasma DPP-4 activity may correlate with aneurysmal development. CD26 on monocytes plays a critical role in cell differentiation, possibly mediated by extracellular signal-regulated protein kinase 1/2-p21 axis signaling pathways and cytoskeletal proteins reassembly. Exploring the role of DPP-4 further may yield potential therapeutic insights.

Topics: Aged; Aged, 80 and over; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Apolipoproteins E; Case-Control Studies; Cell Differentiation; Cell Line, Tumor; Dilatation, Pathologic; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Extracellular Signal-Regulated MAP Kinases; Female; Focal Adhesion Kinase 2; Glucagon-Like Peptide 1; Humans; Macrophages; Male; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Paxillin; RNA Interference; Transfection

The main pathophysiology of abdominal aortic aneurysm (AAA) considerably overlaps with that of atherosclerosis. We reported that incretins [glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP)] or a dipeptidyl peptidase-4 inhibitor (DPP-4I) suppressed atherosclerosis in apolipoprotein E-null (Apoe－/－) mice. Here we investigated the effects of incretin-related agents on AAA in a mouse model.. Apoe－/－ mice maintained on an atherogenic diet were subcutaneously infused with saline, Ang II (2000 ng/kg/min), Ang II, and native GLP-1 (2.16 nmol/kg/day) or Ang II and native GIP (25 nmol/kg/day) for 4 weeks. DPP-4I (MK0626, 6 mg/kg/day) was provided in the diet to the Ang II-infused mice with or without incretin receptor antagonists [(Pro3) GIP and exendin (9-39)].. AAA occurred in 70% of the animals receiving Ang II. DPP-4I reduced this rate to 40% and significantly suppressed AAA dilatation, fibrosis, and thrombosis. In contrast, incretins failed to attenuate AAA. Incretin receptor blockers did not reverse the suppressive effects of DPP-4I on AAA. In the aorta, DPP-4I significantly reduced the expression of Interleukin-1β and increased that of tissue inhibitor of metalloproteinase (TIMP)-2. In addition, DPP-4I increased the ratio of TIMP-2 to matrix metalloproteinases-9.. DPP-4I, MK0626, but not native incretins has protective effects against AAA in Ang II-infused Apoe－/－ mice via suppression of inflammation, proteolysis, and fibrosis in the aortic wall.

Topics: Angiotensin II; Animals; Aorta; Aortic Aneurysm, Abdominal; Apolipoproteins E; Blood Pressure; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Gene Expression Regulation; Glucagon-Like Peptide 1; Incretins; Inflammation; Interleukin-1beta; Male; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Plaque, Atherosclerotic; Tissue Inhibitor of Metalloproteinase-2

To demonstrate the protective effect of glucagon-like peptide 1 (GLP-1) signaling on the cardiovascular system, we conducted this study to show that the GLP-1 receptor analog (lixisenatide) could inhibit abdominal aortic aneurysm (AAA) development in rats.. Lixisenatide was injected subcutaneously 7 days after aneurysm preparation. We evaluated reactive oxygen species (ROS) expression by dihydroethidium staining and 8-hydroxydeoxyguanosine (8-OHdG; the oxidation product of DNA) by immunohistochemical staining. We also analyzed the effect of GLP-1 signaling on the inflammatory response. Histopathological examination was done on day 28, and the AAA dilatation ratio was calculated.. On day 14, ROS expression and 8-OHdG-positive cells in the aneurysm walls were seen to have been significantly decreased by lixisenatide treatment. Western blot analysis showed decreased ERK expression. There was significantly reduced tumor necrosis factor-α mRNA expression in the aneurysm walls and CD68-positive cell infiltration in the aneurysm walls. On day 28, it was evident that the lixisenatide had dramatically reduced aneurysm development in the rats.. GLP-1 elevation inhibits AAA development in rats through its anti-oxidant and anti-inflammatory effects. Thus, GLP-1 could be a potent pharmacological target for AAA treatment.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Aortic Aneurysm, Abdominal; Disease Models, Animal; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Injections, Subcutaneous; Male; Molecular Targeted Therapy; Peptides; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction

Abdominal aortic aneurysm (AAA) is a life-threatening situation affecting almost 10% of elders. There has been no effective medication for AAA other than surgical intervention. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown to have a protective effect on cardiovascular disease. Whether DPP-4 inhibitors may be beneficial in the treatment of AAA is unclear. We investigated the effects of DPP-4 inhibitor sitagliptin on the angiotensin II (Ang II)-infused AAA formation in apoE-deficient (apoE-/-) mice. Mice with induced AAA were treated with placebo or 2.5, 5 or 10 mg/kg/day sitagliptin. Ang II-infused apoE-/- mice exhibited a 55.6% incidence of AAA formation, but treatment with sitagliptin decreased AAA formation. Specifically, administered sitagliptin in Ang II-infused mice exhibited decreased expansion of the suprarenal aorta, reduced elastin lamina degradation of the aorta, and diminished vascular inflammation by macrophage infiltration. Treatment with sitagliptin decreased gelatinolytic activity and apoptotic cells in aorta tissues. Sitaglipitn, additionally, was associated with increased levels of plasma active glucagon-like peptide-1 (GLP-1). In vitro studies, GLP-1 decreased reactive oxygen species (ROS) production, cell migration, and MMP-2 as well as MMP-9 activity in Ang II-stimulated monocytic cells. The results conclude that oral administration of sitagliptin can prevent abdominal aortic aneurysm formation in Ang II-infused apoE-/-mice, at least in part, by increasing of GLP-1 activity, decreasing MMP-2 and MMP-9 production from macrophage infiltration. The results indicate that sitagliptin may have therapeutic potential in preventing the development of AAA.

Topics: Angiotensin II; Animals; Aortic Aneurysm, Abdominal; Apolipoproteins E; Apoptosis; Cell Movement; Cells, Cultured; Chemotaxis; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Fibroblasts; Glucagon-Like Peptide 1; Humans; Infusion Pumps, Implantable; Macrophages; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Monocytes; Reactive Oxygen Species; Sitagliptin Phosphate; U937 Cells