Dipeptidyl Peptidase-4 Inhibitor Decreases Abdominal Aortic Aneurysm Formation through GLP-1-Dependent Monocytic Activity in Mice

Abstract

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.

Dipeptidyl peptidase-4 and kidney fibrosis in diabetes

“…In addition to their glucose-lowering action, DPP-4 inhibitors have been demonstrated to play a protective role in cardiovascular diseases, including hypertension [44], abdominal aortic aneurysm [45], cardiomyopathy [46], atherosclerosis [47], and peripheral vascular disease [48], via both GLP-1-dependent and GLP-1-independent pathways due to their diverse, widely distributed, and pleiotropic actions [49]. Many in vivo and in vitro studies also found that DPP-4 inhibitors can prevent organ fibrosis, including cardiac fibrosis [50,51], hepatic fibrosis [52], and kidney fibrosis [53].…”

Hypoxia-Inducible Factor-1α in Smooth Muscle Cells Protects Against Aortic Aneurysms—Brief Report

“…We also found that the lower α-smooth muscle actin (SMA)-positive vascular area in abdominal aortic aneurysmal sections of SMKO mice treated with Ang II and BAPN accompanied with greater incidence of aortic aneurysm, relative to the control ( Figure XVI in the online-only Data Supplement). Because VSMC apoptosis has previously been shown to be a factor in aneurysm formation by multiple groups, 15,16 this result may reflect the reduced number of VSMCs in aneurysmal regions in SMKO mice. However, we could not confirm so many apoptotic VSMCs in abdominal aortic aneurysmal regions in control mice and SMKO mice in this model (data not shown).…”

Bonus Effects of Antidiabetic Drugs: Possible Beneficial Effects on Endothelial Dysfunction, Vascular Inflammation and Atherosclerosis

“…Lu et al . observed that treatment with liraglutide for 1 hr decreases chemotaxis, ROS generation, MMP‐2 and MMP‐9 activities using a human monocyte cell line stimulated with Ang‐II.…”