Fluvastatin reverses endothelial dysfunction and increased vascular oxidative stress in rat adjuvant‐induced arthritis

Abstract

Objective. To investigate the effect of statins on vascular dysfunction in rat adjuvant-induced arthritis (AIA).Methods. Fluvastatin (5 mg/kg/day) was administered orally to rats with AIA, for 21 days after the onset of arthritis. The vasodilatory response to acetylcholine of aortic rings isolated from rats with AIA that were not treated or were treated with fluvastatin and from normal rats was determined. The amounts of 4-hydroxy-2-nonenal (HNE) and nitrotyrosine in aortas were measured by Western blotting. In vitro and in situ superoxide production in aortas was evaluated based on fluorogenic oxidation of dihydroethidium to ethidium. Expression of NAD(P)H components and endothelial nitric oxide synthase (eNOS) in aortas was examined by real-time reverse transcriptase-polymerase chain reaction and Western blotting. Serum levels of tetrahydrobiopterin, a critical eNOS cofactor, were determined by high-performance liquid chromatography.Results. Fluvastatin reversed endothelial dysfunction in AIA without affecting the clinical severity of arthritis or serum cholesterol concentration. Fluvastatin reduced the amounts of HNE and nitrotyrosine in the aorta, and the levels of superoxide expressed in endothelial cells and smooth muscle cells in the tissue, in rats with AIA. NADH-or L-arginine-induced superoxide production was not observed in the aortic samples from fluvastatin-treated rats with AIA. Fluvastatin decreased the levels of expression of messenger RNA for p22phox, a NAD(P)H oxidase component, in the aortas of rats with AIA, but did not affect the expression of eNOS. Serum levels of tetrahydrobiopterin were significantly reduced in rats with AIA, and were increased by administration of fluvastatin.Conclusion. Our findings demonstrate that fluvastatin has potent vascular protective effects in AIA and provide additional scientific rationale for the use of statins to reduce cardiovascular mortality in patients with rheumatoid arthritis.

Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

“…In contrast, the expression of eNOS did not differ between AIA rats and controls. This result is not in accordance with the data of Haruna et al (12,13), who reported increased eNOS expression in aortas from AIA rats with endothelial dysfunction. However, in their study, neither the activity of NOS nor the functional impact of L-NAME was investigated, and it was not determined whether the eNOS overexpression was associated with increased eNOS activity.…”

“…In the present study, we investigated endothelial function in the AIA model, which is commonly accepted as having many histologic and clinical features in common with human RA (31) and which is widely used to predict clinical efficacy of new therapies in RA (32). In accordance with previous studies (12)(13)(14)(15)(16)(33)(34)(35), our data show that endothelial function assessed by the vasodilating response to ACh is impaired in AIA rats. We also demonstrated that endothelial dysfunction correlates with disease activity.…”

“…Only a few studies have investigated the mechanisms involved in endothelial dysfunction in animal models of arthritis. In the model of adjuvant-induced arthritis (AIA), data demonstrated that vessels from AIA rats overproduced superoxide anions (O 2 Ϫ ) (12)(13)(14) and that BH 4 supplementation decreased endothelial dysfunction (12), suggesting that the deficiency in BH 4 may contribute to the uncoupling of eNOS and subsequent production of O 2 Ϫ . However, treatment with vitamin E used as an antioxidant both improved (15) and decreased (16) endothelial function in AIA rats.…”

Telmisartan improves endothelial dysfunction and renal autoregulation in Dahl salt-sensitive rats

“…Fluorescence spectrometry of tissue O 2 -production was carried out using the fluorogenic oxidation of DHE to ethidium as a measure of O 2 -, as previously described. 16 The renal cortex of the right kidney obtained from each rat was cut into small pieces, and the glomeruli were isolated by the mechanical graded sieving technique. After isolation, the purity of the final suspension was determined by light microscopic examination.…”

“…We used Dahl salt-sensitive hypertensive (DS) rats to examine the NOS coupling statement in the kidney using the dihydroethidium (DHE) assay 16 and in vivo NO and ROS imaging, 17 and examined autoregulation capacity by measuring renal microvascular responses to step changes in renal perfusion pressure. Moreover, to elucidate whether angiotensin receptor blockade (ARB) has a beneficial effect against eNOS uncoupling and renal autoregulation, we examined DS rats treated with telmisartan, an angiotensin receptor blocker.…”