8-hydroxy-2--deoxyguanosine and Dilatation--Pathologic

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.. 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.. 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).. 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.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Animals; Antioxidants; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Calcium Chloride; Deoxyguanosine; Dilatation, Pathologic; Disease Models, Animal; DNA Damage; Enzyme Activation; Enzyme Activators; Extracellular Signal-Regulated MAP Kinases; Inflammation Mediators; Male; Matrix Metalloproteinase 9; Oxidative Stress; Pancreatic Elastase; Rats, Sprague-Dawley; Reactive Oxygen Species; Riboflavin; Superoxide Dismutase; Time Factors

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.. 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.. 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 < .001). On day 28 (six in each group), the aortic wall in groups LD and HD was less dilated (dilatation ratio: 199.2% ± 11.8% in group C, 159.6% ± 2.8% in group LD, and 147.1% ± 1.9% in group HD; P < .02 group C vs HD) and had higher elastin content than in group C. The difference in blood glucose levels among the three groups was not significant.. The DPP-4 inhibitor, alogliptin, attenuates aneurysm formation and expansion dose-dependently in a rat AAA model via an antioxidative action.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Animals; Antioxidants; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Blood Glucose; Calcium Chloride; Deoxyguanosine; Dilatation, Pathologic; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; DNA Damage; Dose-Response Relationship, Drug; Gene Expression Regulation, Enzymologic; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Oxidative Stress; Pancreatic Elastase; Piperidines; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA, Messenger; Time Factors; Uracil

Oxidative stress (OS) is related to vascular inflammation possibly, contributing to the development of coronary ectasia (CE). Base excision repair (BER) and nucleotide excision repair are the main DNA repair pathways that can help to remove 8-hydroxydeoxyguanine (8-OHdG), a marker of OS. Human 8-oxoguanine DNA glycosylase 1 (hOGG1) is a key enzyme of the BER pathway and catalyzes the removal of 8-OHdG. The aim of our study was to investigate the association between hOGG1 Ser326Cys gene polymorphism and CE in a Chinese population. Five-hundred forty-seven patients who underwent diagnostic coronary angiography in a tertiary medical center were recruited. The angiographic definition of CE is the diameter of the ectatic segment being more than 1.5 times larger compared with an adjacent healthy reference segment. The gene polymorphisms were analyzed by polymerase chain reaction. The urine 8OHdG concentration was measured using a commercial ELISA kit. The distribution of hOGG1 Ser326Cys genotypes was significantly different between CE and non-CE groups (p = 0.033). The odds ratio of CE development for the Ser to the Cys variant was 1.55 (95% confidence interval (CI), 1.04-2.31, p = 0.033). Both univariate and logistic regression analysis showed a significant association of hOGG1 Ser326Cys polymorphism in the dominant model with CE development (p = 0.009 and 0.011, respectively). Urine 8-OHdG levels were significantly higher in subjects carrying the hOGG1 Ser variant than in those with the Cys/Cys genotype (p < 0.03). In conclusion, our study suggests that the hOGG1 Ser326Cys gene variant might play a role in susceptibility to the development of CE.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Case-Control Studies; China; Coronary Artery Disease; Deoxyguanosine; Dilatation, Pathologic; DNA Glycosylases; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Mutation, Missense; Polymorphism, Single Nucleotide; Radiography

An ideal pharmaceutical treatment for abdominal aortic aneurysm (AAA) is to prevent aneurysm formation and development (further dilatation of pre-existing aneurysm). Recent studies have reported that oxidative stress with reactive oxygen species (ROS) is crucial in aneurysm formation. We hypothesized that edaravone, a free-radical scavenger, would attenuate vascular oxidative stress and inhibit AAA formation and development.. An AAA model induced with intraluminal elastase and extraluminal calcium chloride was created in 42 rats. Thirty-six rats were divided three groups: a low-dose (group LD; 1 mg/kg/d), high-dose (group HD; 5 mg/kg/d), and control (group C, saline). Edaravone or saline was intraperitoneally injected twice daily, starting 30 minutes before aneurysm preparation. The remaining six rats (group DA) received a delayed edaravone injection (5 mg/kg/d) intraperitoneally, starting 7 days after aneurysm preparation to 28 days. AAA dilatation ratio was calculated. Pathologic examination was performed. ROS expression was semi-quantified by dihydroethidium staining and the oxidative product of DNA induced by ROS, 8-hydroxydeoxyguanosine (8-OHdG), by immunohistochemical staining.. At day 7, ROS expression and 8-OHdG-positive cells in aneurysm walls were decreased by edaravone treatment (ROS expression: 3.0 ± 0.5 in group LD, 1.7 ± 0.3 in group HD, and 4.8 ± 0.7 in group C; 8-OHdG-positive cells: 106.2 ± 7.8 cells in group LD, 64.5 ± 7.7 cells in group HD, and 136.6 ± 7.4 cells in group C; P < .0001), compared with group C. Edaravone treatment significantly reduced messenger RNA expressions of cytokines and matrix metalloproteinases (MMPs) in aneurysm walls (MMP-2: 1.1 ± 0.5 in group LD, 0.6 ± 0.1 in group HD, and 2.3 ± 0.4 in group C; P < .001; MMP-9: 1.2 ± 0.1 in group LD, 0.2 ± 0.6 in group HD, and 2.4 ± 0.2 in group C; P < .001). At day 28, aortic walls in groups LD and HD were less dilated, with increased wall thickness and elastin content than those in group C (dilatation ratio: 204.7% ± 16.0% in group C, 156.5% ± 6.6% in group LD, 136.7% ± 2.0% in group HD; P < .0001). Delayed edaravone administration significantly prevented further aneurysm dilatation, with increased elastin content (155.2% ± 2.9% at day 7, 153.1% ± 11.6% at day 28; not significant).. Edaravone inhibition of ROS can prevent aneurysm formation and expansion in the rat AAA model. Free-radical scavenger edaravone might be an effective pharmaceutical agent for AAA in clinical practice.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antipyrine; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Apoptosis; Biomarkers; Calcium Chloride; Deoxyguanosine; Dilatation, Pathologic; Disease Models, Animal; Disease Progression; Drug Administration Schedule; Edaravone; Elastin; Free Radical Scavengers; Gene Expression Regulation; Immunohistochemistry; Injections, Intraperitoneal; Interleukin-1beta; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Oxidative Stress; Pancreatic Elastase; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Time Factors; Tumor Necrosis Factor-alpha