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Early treatment with hydroxychloroquine prevents the development of endothelial dysfunction in a murine model of systemic lupus erythematosus.

Virdis A, Tani C, Duranti E, Vagnani S, Carli L, Kühl AA, Solini A, Baldini C, Talarico R, Bombardieri S, Taddei S, Mosca M - Arthritis Res. Ther. (2015)

Bottom Line: Beyond the beneficial effect in well-established disease, our hypothesis is that treatment with HCQ might have a beneficial impact on ED prevention in SLE.Starting from 18 weeks of age, NZ mice showed a progressive reduction in NO availability, which was normalized by ascorbic acid and apocynin in the up to 24-week-old group, and partly ameliorated in older animals.Very early treatment with HCQ is able to exert vascular protection via an antioxidant effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. agostino.virdis@med.unipi.it.

ABSTRACT

Introduction: Accelerated atherosclerosis is one of the major causes of morbidity in patients with systemic lupus erythematosus (SLE). Endothelial dysfunction (ED) is considered an early marker of atherosclerosis. It is a reversible alteration, thus representing an attractive target for prevention strategies against cardiovascular disease. Studies have shown that ED occurs in patients with SLE even in the absence of severe, active disease. Hydroxychloroquine (HCQ) is widely used in SLE to control disease activity, but its use is also associated with an improvement in long-term prognosis. Beyond the beneficial effect in well-established disease, our hypothesis is that treatment with HCQ might have a beneficial impact on ED prevention in SLE. The aim of this study was to assess the impact of early treatment with HCQ on ED in a murine model of SLE.

Methods: Twelve-week-old NZB/W F1 (NZ) and C57BL/6 J mice (controls) were allocated to receive HCQ or vehicle for 6, 12, or 18 weeks. Proteinuria and anti-double-stranded DNA autoantibodies were determined. ED was assessed in mesenteric arteries (pressurized myography). Nitric oxide (NO) availability and reactive oxygen species (ROS) production were evaluated. Vascular ROS production was measured with dihydroethidium (DHE) fluorescent dye.

Results: Starting from 18 weeks of age, NZ mice showed a progressive reduction in NO availability, which was normalized by ascorbic acid and apocynin in the up to 24-week-old group, and partly ameliorated in older animals. HCQ administration normalized the NO availability in the up to 24-week-old group, with a partial amelioration in the 30-week-old group. DHE analysis revealed a progressive increment of vascular ROS generation among NZ groups, which was prevented by apocynin. Similarly, in the NZ HCQ-treated group, vascular ROS production was abrogated.

Conclusions: The ED that characterizes this mouse model of SLE is caused by the nicotinamide adenine dinucleotide phosphate oxidase-driven ROS excess. Very early treatment with HCQ is able to exert vascular protection via an antioxidant effect.

No MeSH data available.


Related in: MedlinePlus

Relaxations in response to acetylcholine in mesenteric arteries at baseline and different time points in control mice (a), NZB/W F1 mice (NZ) (b) or NZB/W F1 mice treated with hydroxychloroquine (NZ-HCQ) (c). Each point represents the mean ± SEM of eight experiments. *P < 0.05; †P < 0.01
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Fig2: Relaxations in response to acetylcholine in mesenteric arteries at baseline and different time points in control mice (a), NZB/W F1 mice (NZ) (b) or NZB/W F1 mice treated with hydroxychloroquine (NZ-HCQ) (c). Each point represents the mean ± SEM of eight experiments. *P < 0.05; †P < 0.01

Mentions: In Ctrl animals, relaxation in response to ACh was preserved up to week 24 (Emax ACh, 12 weeks: 99.7 ± 0.6 %; 18 weeks: 99.8 ± 0.4 %; 24 weeks: 99.6 ± 0.7 %), but it was attenuated at week 30 (90.0 ± 0.9 %) (Fig. 2a). l-NAME significantly blunted the relaxation in response to ACh at baseline and until 30 weeks, when a reduced inhibitory effect emerged (Fig. 3). Moreover, ascorbic acid was ineffective in changing the vascular response to ACh at baseline (Emax ACh + ascorbic acid: 99.1 ± 0.4 %) and until 30 weeks (Emax ACh + ascorbic acid, 12 weeks: 98.2 ± 0.7 %; 24 weeks: 98.4 ± 0.9 %; 30 weeks: 98.3 ± 0.6 %), when it normalized the relaxation response to ACh (Emax ACh + ascorbic acid: 96.9 ± 0.4 %) and restored the inhibitory effect of l-NAME on ACh (54.8 ± 0.9 %).Fig. 2


Early treatment with hydroxychloroquine prevents the development of endothelial dysfunction in a murine model of systemic lupus erythematosus.

Virdis A, Tani C, Duranti E, Vagnani S, Carli L, Kühl AA, Solini A, Baldini C, Talarico R, Bombardieri S, Taddei S, Mosca M - Arthritis Res. Ther. (2015)

Relaxations in response to acetylcholine in mesenteric arteries at baseline and different time points in control mice (a), NZB/W F1 mice (NZ) (b) or NZB/W F1 mice treated with hydroxychloroquine (NZ-HCQ) (c). Each point represents the mean ± SEM of eight experiments. *P < 0.05; †P < 0.01
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4594997&req=5

Fig2: Relaxations in response to acetylcholine in mesenteric arteries at baseline and different time points in control mice (a), NZB/W F1 mice (NZ) (b) or NZB/W F1 mice treated with hydroxychloroquine (NZ-HCQ) (c). Each point represents the mean ± SEM of eight experiments. *P < 0.05; †P < 0.01
Mentions: In Ctrl animals, relaxation in response to ACh was preserved up to week 24 (Emax ACh, 12 weeks: 99.7 ± 0.6 %; 18 weeks: 99.8 ± 0.4 %; 24 weeks: 99.6 ± 0.7 %), but it was attenuated at week 30 (90.0 ± 0.9 %) (Fig. 2a). l-NAME significantly blunted the relaxation in response to ACh at baseline and until 30 weeks, when a reduced inhibitory effect emerged (Fig. 3). Moreover, ascorbic acid was ineffective in changing the vascular response to ACh at baseline (Emax ACh + ascorbic acid: 99.1 ± 0.4 %) and until 30 weeks (Emax ACh + ascorbic acid, 12 weeks: 98.2 ± 0.7 %; 24 weeks: 98.4 ± 0.9 %; 30 weeks: 98.3 ± 0.6 %), when it normalized the relaxation response to ACh (Emax ACh + ascorbic acid: 96.9 ± 0.4 %) and restored the inhibitory effect of l-NAME on ACh (54.8 ± 0.9 %).Fig. 2

Bottom Line: Beyond the beneficial effect in well-established disease, our hypothesis is that treatment with HCQ might have a beneficial impact on ED prevention in SLE.Starting from 18 weeks of age, NZ mice showed a progressive reduction in NO availability, which was normalized by ascorbic acid and apocynin in the up to 24-week-old group, and partly ameliorated in older animals.Very early treatment with HCQ is able to exert vascular protection via an antioxidant effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. agostino.virdis@med.unipi.it.

ABSTRACT

Introduction: Accelerated atherosclerosis is one of the major causes of morbidity in patients with systemic lupus erythematosus (SLE). Endothelial dysfunction (ED) is considered an early marker of atherosclerosis. It is a reversible alteration, thus representing an attractive target for prevention strategies against cardiovascular disease. Studies have shown that ED occurs in patients with SLE even in the absence of severe, active disease. Hydroxychloroquine (HCQ) is widely used in SLE to control disease activity, but its use is also associated with an improvement in long-term prognosis. Beyond the beneficial effect in well-established disease, our hypothesis is that treatment with HCQ might have a beneficial impact on ED prevention in SLE. The aim of this study was to assess the impact of early treatment with HCQ on ED in a murine model of SLE.

Methods: Twelve-week-old NZB/W F1 (NZ) and C57BL/6 J mice (controls) were allocated to receive HCQ or vehicle for 6, 12, or 18 weeks. Proteinuria and anti-double-stranded DNA autoantibodies were determined. ED was assessed in mesenteric arteries (pressurized myography). Nitric oxide (NO) availability and reactive oxygen species (ROS) production were evaluated. Vascular ROS production was measured with dihydroethidium (DHE) fluorescent dye.

Results: Starting from 18 weeks of age, NZ mice showed a progressive reduction in NO availability, which was normalized by ascorbic acid and apocynin in the up to 24-week-old group, and partly ameliorated in older animals. HCQ administration normalized the NO availability in the up to 24-week-old group, with a partial amelioration in the 30-week-old group. DHE analysis revealed a progressive increment of vascular ROS generation among NZ groups, which was prevented by apocynin. Similarly, in the NZ HCQ-treated group, vascular ROS production was abrogated.

Conclusions: The ED that characterizes this mouse model of SLE is caused by the nicotinamide adenine dinucleotide phosphate oxidase-driven ROS excess. Very early treatment with HCQ is able to exert vascular protection via an antioxidant effect.

No MeSH data available.


Related in: MedlinePlus