Endogenous superoxide dismutase activation by oral administration of riboflavin reduces abdominal aortic aneurysm formation in rats

• Published in: Journal of vascular surgery Vol. 64; no. 3; pp. 737 - 745
• Main Authors: Yu, Zhenhai, MD, Morimoto, Keisuke, MD, PhD, Yu, Jie, MD, Bao, Wulan, MD, PhD, Okita, Yutaka, MD, PhD, Okada, Kenji, MD, PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2016
• 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 - pathology; Aortic Aneurysm, Abdominal - prevention & control; Calcium Chloride; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - metabolism; Dilatation, Pathologic; Disease Models, Animal; DNA Damage; Enzyme Activation; Enzyme Activators - administration & dosage; Extracellular Signal-Regulated MAP Kinases - metabolism; Inflammation Mediators - metabolism; Male; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Oxidative Stress - drug effects; Pancreatic Elastase; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Riboflavin - administration & dosage; Superoxide Dismutase - metabolism; Surgery; Time Factors
• ISSN: 0741-5214; 1097-6809
• DOI: 10.1016/j.jvs.2015.03.045

Objective Vitamin B2 (riboflavin) reportedly has an antioxidant effect through superoxide dismutase (SOD) activation. However, the effect of riboflavin on abdominal aortic aneurysm (AAA) has never been investigated. In the present study, we examined the hypothesis that riboflavin has a protective effect on AAA formation in an experimental rat model. Methods The AAA model, which was induced with intraluminal elastase and extraluminal calcium chloride, was created in 36 rats. The 36 rats were divided into a riboflavin group (group R; 25 mg/kg/d), and control group (carboxymethyl cellulose). Riboflavin administration by gastric gavage once per day was started at 3 days before aneurysm preparation. On day 3, SOD activity in aneurysm walls was assayed. On day 7, reactive oxygen species (ROS) levels were semiquantified by dihydroethidium staining, and the oxidation product of DNA produced by ROS, 8-hydroxydeoxyguanosine (8-OHdG), was measured by immunohistochemical staining. Histopathologic examination (hematoxylin/eosin and elastica Van Gieson staining) was performed on day 28, and the AAA dilatation ratio was calculated to evaluate the protective effect of riboflavin. Results On day 3, SOD activity was significantly increased in aneurysm walls by riboflavin administration (370 ± 204 U/mL in normal, 334 ± 86 U/mL in control, 546 ± 143 U/mL in group R; P  = .021). On day 7, ROS levels and 8-OHdG-positive cells in aneurysm walls were significantly decreased by riboflavin treatment (ROS levels: 1.0 ± 0.1 in normal, 4.5 ± 0.4 in control, 3.1 ± 0.5 in group R, P  < .01; 8-OHdG-positive cells: 30 ± 2 cells in normal, 148 ± 20 cells in control, 109 ± 15 cells in group R, P  < .01). Riboflavin treatment significantly reduced matrix metalloproteinase (MMP)-9 messenger RNA expression in aneurysm walls (relative expression: MMP-9: 0.4 ± 0.7 in normal, 2.6 ± 1.3 in control, 0.5 ± 0.3 in group R, P  < .01). On day 28, the aortic walls were less dilated and had higher elastin content in group R than in control (dilatation ratio: 194.9% ± 10.9% in control, 158.6% ± 2.5% in group R; P  <.01). Conclusions Riboflavin treatment prevents AAA formation in a rat model through an antioxidant effect and might be a potent pharmacologic agent for AAA treatment in clinical practice.