Orally administered dipeptidyl peptidase-4 inhibitor (alogliptin) prevents abdominal aortic aneurysm formation through an antioxidant effect in rats

• Published in: Journal of vascular surgery 2014-04, Vol.59 (4), p.1098-1108
• Main Authors: Bao, Wulan, MD, Morimoto, Keisuke, MD, Hasegawa, Tomomi, MD, PhD, Sasaki, Naoto, MD, PhD, Yamashita, Tomoya, MD, PhD, Hirata, Kenichi, MD, PhD, Okita, Yutaka, MD, PhD, Okada, Kenji, MD, PhD
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antioxidants - administration & dosage; Aorta, Abdominal - drug effects; Aorta, Abdominal - enzymology; Aorta, Abdominal - pathology; Aortic Aneurysm, Abdominal - chemically induced; Aortic Aneurysm, Abdominal - enzymology; Aortic Aneurysm, Abdominal - genetics; Aortic Aneurysm, Abdominal - pathology; Aortic Aneurysm, Abdominal - prevention & control; Blood Glucose - drug effects; Blood Glucose - metabolism; Calcium Chloride; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - metabolism; Dilatation, Pathologic; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl-Peptidase IV Inhibitors - administration & dosage; Disease Models, Animal; DNA Damage; Dose-Response Relationship, Drug; Gene Expression Regulation, Enzymologic - drug effects; Male; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Oxidative Stress - drug effects; Pancreatic Elastase; Piperidines - administration & dosage; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; RNA, Messenger - metabolism; Surgery; Time Factors; Uracil - administration & dosage; Uracil - analogs & derivatives
• ISSN: 0741-5214; 1097-6809
• DOI: 10.1016/j.jvs.2013.04.048

Objective Dipeptidyl peptidase-4 (DPP-4) inhibitor, a novel antidiabetic drug, has a cardioprotective effect on ischemia-reperfusion injury through an antioxidant effect. However, the effect of DPP-4 inhibitor on aneurysm formation has not been investigated. We aimed to test the hypothesis that the DPP-4 inhibitor, alogliptin, attenuates vascular oxidative stress and thus inhibits abdominal aortic aneurysm (AAA) formation. Methods AAAs were created with intraluminal elastase and extraluminal calcium chloride in 36 male rats. Rats were divided into three groups: a low dose of alogliptin group (group LD; 1 mg/kg/d), a high-dose group (group HD; 3 mg/kg/d), and a control group (group C, water). Alogliptin was administered by gastric gavage once daily beginning 3 days before surgery. On day 7 after aneurysm preparation, reactive oxygen species (ROS) expression was semiquantified by dihydroethidium staining, and the oxidation product of DNA produced by ROS, 8-hydroxydeoxyguanosine (8-OHdG), was measured by immunohistochemical staining. Blood glucose concentrations were measured. Hematoxylin and eosin and elastica Van Gieson stainings were performed on day 28, and the AAA dilatation ratio was calculated. Results On day 7 (six in each group), dihydroethidium staining of the aneurysm wall showed a reduced level of ROS expression (4.6 ± 0.6 in group C, 2.7 ± 0.3 in group LD, and 1.7 ± 0.5 in group HD; P  < .0001) and showed fewer 8-OHdG-positive cells in alogliptin-treated samples (138.1 ± 7.4 cells in group C, 102.5 ± 4.5 cells in group LD, and 66.1 ± 4.5 cells in group HD; P  < .0001) The treatment significantly reduced messenger RNA expression of matrix metalloproteinases (MMPs) in aneurysm walls (relative expression: MMP-2: 2.1 ± 0.4 in group C, 1.3 ± 0.3 in group LD, and 0.9 ± 0.2 in group HD; P  < .001; MMP-9: 2.0 ± 0.5 in group C, 0.3 ± 0.3 in group LD, and 0.3 ± 0.2 in group HD; P