Vitamins Reverse Endothelial Dysfunction Through Regulation of eNOS and NAD(P)H Oxidase Activities

Antioxidant vitamins C and E have protective properties in genetic hypertension associated with enhanced oxidative stress. This study investigated whether vitamins C and/or E modulate vascular function by regulating enzymatic activities of endothelial nitric oxide synthase (eNOS) and NAD(P)H oxidase using thoracic aortas of 20- to 22-week-old male spontaneously hypertensive rats (SHR) and their matched normotensive counterparts, Wistar-Kyoto rats (WKY). SHR aortas had impaired relaxant responses to acetylcholine but not to sodium nitroprusside, despite an 2-fold increase in eNOS activity and NO release. The levels of superoxide anion (O2 ), a potent NO scavenger, and NAD(P)H oxidase activity were also 2-fold higher in SHR aortas. Mechanical but not pharmacological inactivation of endothelium (by rubbing and 100 mol/L L-NAME, respectively) significantly abrogated O2 in both strains. Treatments of SHR aortas with NAD(P)H oxidase inhibitors, namely diphenyleneiodinium and apocynin, significantly diminished O2 production. The incubation of SHR aortas with different concentrations of vitamin C (10 to 100 mol/L) and specifically with high concentrations of vitamin E (100 mol/L) improved endothelial function, reduced superoxide production as well as NAD(P)H oxidase activity, and increased eNOS activity and NO generation in SHR aortas to the levels observed in vitamin C- and E-treated WKY aortas. Our results reveal endothelial NAD(P)H oxidase as the major source of vascular O2 in SHR and also show that vitamins C and E are critical in normalizing genetic endothelial dysfunction through regulation of eNOS and NAD(P)H oxidase activities

Internal mammary artery smooth muscle cells resist migration and possess high antioxidant capacity

Objective- This study investigated whether differences exist in atherogen-induced migratory behaviors and basal antioxidant enzyme capacity of vascular smooth muscle cells (VSMC) from human coronary (CA) and internal mammary (IMA) arteries. Methods- Migration experiments were performed using the Dunn chemotaxis chamber. The prooxidant [NAD(P)H oxidase] and antioxidant [NOS, superoxide dismutase, catalase and glutathione peroxidase] enzyme activities were determined by specific assays. Results- Chemotaxis experiments revealed that while both sets of VSMC migrated towards platelet-derived growth factor-BB (1-50 ng/ml) and angiotensin II (1-50 nM), neither oxidized-LDL (ox-LDL, 25-100 �g/ml) nor native LDL (100 �g/ml) affected chemotaxis in IMA VSMC. However, high dose ox-LDL produced significant chemotaxis in CA VSMC that was inhibited by pravastatin (100 nM), mevastatin (10 nM), losartan (10 nM), enalapril (1 �M), and MnTBAP (a free radical scavenger, 50��M). Microinjection experiments with isoprenoids i.e. geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP) showed distinct involvement of small GTPases in atherogen-induced VSMC migration. Significant increases in antioxidant enzyme activities and nitrite production along with marked decreases in NAD(P)H oxidase activity and O2 .- levels were determined in IMA versus CA VSMC. Conclusions- Enhanced intrinsic antioxidant capacity may confer on IMA VSMC resistance to migration against atherogenic agents. Drugs that regulate ox-LDL or angiotensin II levels also exert antimigratory effects

Role of gender, smoking profile, hypertension, and diabetes on saphenous vein and internal mammary artery endothelial relaxation in patients with coronary artery bypass grafting

The aim of this study was to investigate if there was a link between the relaxant responses in saphenous vein (SV) and internal mammary artery (IMA) segments obtained from patients undergoing coronary artery bypass grafting and the patients' cardiovascular risk factors. Endothelium-(in)dependent relaxations were assessed by isometric tension studies. Endothelium-dependent relaxant responses were greater in IMA than SV and gender, smoking profile and history of hypertension but not diabetes appeared to have an influence on these responses. Endothelium-dependent relaxant responses in both IMA and SV were greater in males than females and relaxant responses in IMA segments were attenuated in smokers, whereas the opposite effect was noted in SV segments. Endothelium-dependent relaxant responses in SV were lower in patients with hypertension. Endothelium-independent relaxant responses were greater in IMA than SV. Endothelium-independent responses were greater in male patients' SV segments, but gender played no role in IMA segments. Diabetes had no effect on endothelium-independent responses in IMA, but SV segments from diabetic patients had greater responses. Neither conduit's endothelium-independent response was affected by hypertensive status. The relationship between risk factor status and endothelial responses is multifactorial, with gender, hypertension, diabetes and smoking status all contributing

Representation, Verification, and Visualization of Tarskian Interpretations for Typed First-order Logic

peer reviewedThis paper describes a new format for representing Tarskian-style interpretations for formulae in typed first-order logic, using the TPTP TF0 language. It further describes a technique and an implemented tool for verifying models using this representation, and a tool for visualizing interpretations. The research contributes to the advancement of automated reasoning technology for model finding, which has several applications, including verification