Objective. To investigate endothelial function and levels of vascular oxidative stress in rat adjuvantinduced arthritis (AIA), in view of mounting evidence for an association between rheumatoid arthritis (RA) and accelerated vascular disease.Methods. Thoracic aortic rings were prepared from AIA and control rats. After preconstriction by norepinephrine, the vasodilatory response to acetylcholine was determined. The amounts of 4-hydroxy-2-nonenal (HNE) and nitrotyrosine in AIA rat aortas were measured by Western blotting. Homogenates of the aortas were incubated with various substrates for superoxide-producing enzymes, and superoxide production was assessed by fluorogenic oxidation of dihydroethidium to ethidium. Expression of endothelial nitric oxide synthase (eNOS) in aortas was examined by real-time reverse transcriptase-polymerase chain reaction and Western blotting. Serum levels of tetrahydrobiopterin (BH 4 ), a critical eNOS cofactor, were determined by high-performance liquid chromatography.Results. Endothelium-dependent relaxation of the aortic ring was significantly depressed in AIA rats compared with control rats. The amounts of HNE and nitrotyrosine were increased in AIA rat aortas, indicating overproduction of reactive oxygen species. Incubation of AIA rat aorta homogenates with NADH or L-arginine, a substrate of eNOS, resulted in a significant increase in superoxide production. Endothelial NOS was highly expressed in AIA rat aortas. Serum levels of BH 4 were significantly lower in AIA. Treatment of AIA with BH 4 reversed the endothelial dysfunction, suggesting that its deficiency may contribute to the uncoupling of eNOS.Conclusion. Vascular dysfunction in RA can be partially modeled in animals. NAD(P)H oxidase and uncoupled eNOS are responsible for the increase in vascular oxidative stress, which is likely to be involved in the endothelial dysfunction in AIA.

Objective. To explore the involvement of the renin-angiotensin system (RAS) in the development of vascular damage in adjuvant-induced arthritis (AIA) in rats.Methods. Angiotensin II (Ang II; 0.25 or 1.0 mg/kg/day) was infused in control rats and rats with AIA for 21 days, and the impact of systemic inflammation on Ang II-induced hypertension, endothelial dysfunction, and vascular hypertrophy was evaluated. Expression of angiotensin II type 1 receptor (AT 1 R) and angiotensin-converting enzyme (ACE) in the aortas of rats with AIA were examined by real-time polymerase chain reaction (PCR) and Western blot analyses. Losartan (3 mg/kg/day) or irbesartan (5 mg/kg/day), both of which are AT 1 R blockers, was administered orally to rats with AIA for 21 days. In situ superoxide production in aortas was assessed according to the fluorogenic oxidation of dihydroethidium to ethidium. The expression and activity of NAD(P)H oxidases in aortas were examined by real-time PCR analysis and lucigenin chemiluminescence assay. Endothelial function in rats with AIA treated in vivo or ex vivo with AT 1 R blockers was also determined.Results. The Ang II-induced hypertensive response, endothelial dysfunction, and vascular hypertrophy were exacerbated in rats with AIA. Expression of AT 1 R and ACE was increased in the aortas of rats with AIA. Both losartan and irbesartan decreased the levels of superoxide and the expression and activity NAD(P)H oxidases in the aortas of rats with AIA. The endothelial dysfunction in AIA was improved by the in vivo or ex vivo treatment with AT 1 R blockers.Conclusion. The locally activated RAS is involved in the increased vascular oxidative stress and endothelial dysfunction in AIA. Our findings have important implications for clinical approaches to the reduction of cardiovascular risk in patients with rheumatoid arthritis.

Lower adiponectin levels in circulation are shown to be associated with endothelial dysfunction, which is a crucial feature in the evolution of atherosclerosis. The aim of our study is to evaluate the effect of anti-tumor necrosis factor (TNF) therapy on adiponectin levels with endothelial function and arterial stiffness. Fifteen Japanese patients with rheumatoid arthritis (RA) received infusions with infliximab (3 mg/kg) at weeks 0, 2, and 6. Serum concentrations of adiponectin, endothelial function, and pulse wave velocity (PWV) were measured before each infusion. Endothelium-dependent vasodilatation and endothelium-independent vasodilatation were evaluated as forearm blood flow response to reactive and nitroglycerin-induced hyperemia using strain-gauge plethysmography. Endothelium-dependent vasodilatation was significantly improved at 2 weeks and 6 weeks by treatment with infliximab. PWV remained unchanged. Anti-TNF therapy significantly increased serum adiponectin levels at 2 weeks and 6 weeks. The adiponectin levels were positively correlated with the endothelium-dependent vasodilatation, and negatively with the disease activity score of 28 joints. Our study shows a short-term efficacy of infliximab on adiponectin levels and endothelial dysfunction of patients with RA, and provides additional evidence to support the regulatory role of TNF-alpha on the expression of adiponectin in vivo.

Renal sympathetic denervation helps to protect against glomerular sclerosis, possibly by suppressing NAD(P)H oxidase activity, thereby decreasing glomerular reactive oxygen species.

It is important to consider a strategy to halt the development of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Oral adsorbent AST-120 retards deterioration in renal function, reducing indoxyl sulfate (IS) accumulation. The aim of this study was to determine whether AST-120 improves endothelial dysfunction by reducing oxidative/nitrative stress in a rat-CKD model. Subtotally nephrectomized (Nx) rats aged 17 weeks were divided into two groups: control rats and rats orally treated with AST-120. Two weeks after initiation of AST-120, serum and urinary IS levels, renal histological scores and endothelium-dependent vascular responses (EDVRs) in the aorta were investigated. EDVR in 5-h incubation with 250 lg ml À1 IS was also examined in normal rat aortas. Nitrotyrosine content, mRNA expression of p47phox, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase component, and expression and phosphorylation (serine-1177) of endothelial nitric oxide synthase (eNOS) in the aorta were examined in untreated and treated Nx rats. At the end of treatment, renal function and histological scores were not different in the two groups. AST-120 prevented the elevation of serum IS level in Nx rats, reducing urinary IS excretion, and ameliorated decreased EDVR in Nx rats. Incubation with IS tended to reduce EDVR in normal aortas, albeit insignificantly. AST-120 also suppressed nitrotyrosine accumulation and inhibited p47phox expression in Nx rats. The eNOS expression and phosphorylation were similar in the two groups. In conclusion, AST-120 ameliorated endothelial dysfunction and alleviated oxidative/nitrative stress in the aorta through reduced accumulation of IS, independent of renal function, in a rat CKD model.