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Chronic hydroxychloroquine improves endothelial dysfunction and protects kidney in a mouse model of systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that affects various organs. Women with SLE exhibit a high prevalence of hypertension and renal injury. Antimalarial drugs remain the first-line treatment for patients with mild SLE along with nonsteroidal anti-inflammatory drugs. Hydroxychloroquine (HCQ), antimalarial drug, inhibits phagosome function, thereby inhibiting Toll-like receptors activation leading to a down-regulation of interferon-α and decreasing the antigen processing necessary for autoantigen presentation (Yildirim-Toruner et al., 2011). HCQ has also a beneficial effect on dyslipidemia. However, it has never analyzed whether these underlying mechanisms prevent the cardiovascular complications remained in this disease. Thus, the aim of the present study was to analyze the effects of HCQ on hypertension, endothelial dysfunction and renal injury in a female mouse model of SLE. Thirty five-week old SLE (NZBWF1) and control (NZW/LacJ) mice were treated with HCQ 10 mg/kg/day by oral gavage for 5 weeks. Systolic blood pressure (SBP) was measured in conscious mice by tail-cuff plethysmography. At the end of the treatment, vascular reactivity was assessed using descending thoracic aortic rings mounted in an isometric wire myograph. The renal injury was assessed by measurement the proteinuria levels by Bradford method. Plasma ds-DNA antibodies were measured by a commercial ELISA and only mice NZBWF1 with positive anti-dsDNA antibodies were considered to have SLE. Results are expressed as means with their standard errors. Statistically significant differences were calculated by two-way ANOVA analysis followed by Bonferroni post hoc test. SLE mice had increased BPS compared with controls (128 ± 3 vs 104 ± 2 mmHg, respectively, p<0.01). HCQ treatment did not modify the hypertension SLE mice (125 ± 3 mmHg) but prevented the cardiac and renal hypertrophy. Aortae from SLE mice showed strongly reduced endothelium-dependent vasodilator responses to acetylcholine (Maximal effect = 22.7 ± 6.6% and 42.0 ± 6.1%, respectively, p<0.05). The treatment with HCQ showed an increase in the vasodilation induced by acetylcholine as compared to SLE mice (Maximal effect = 57.5 ± 6.2%, p<0.01). These relaxant responses were suppressed by incubation for 30 min with the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10− 4 M) in all experimental groups. In aortic rings, no differences were observed among groups in the endothelium-independent vasodilator responses to NO donor sodium nitroprusside. The increase in vasoconstriction induced by phenylephrine (10-6 M) when the rings were incubated previously with L-NAME was significantly reduced in aortae from SLE mice compared with control animals (5.2 ± 6.6% vs 31.0 ± 8.0%, p<0.05), indicating a reduced basal NO formation in SLE mice. HCQ increases this contractile response (40.3 ± 10.1%, p<0.05), suggesting a higher NO formation in these vessels compared with those from SLE mice. Urinary protein excretion was increased in SLE mice compared with controls (166 ± 34 vs 62 ± 11 mg/24h/100g, respectively, p<0.01) and significantly (p<0.05) reduced with HCQ treatment (77 ± 11 mg/24h/100g). Total plasma anti-ds-DNA antibodies were significantly (p<0.01) greater in SLE mice than control group (122 ± 11 vs 76 ± 8 ng/mL, respectively) and the treatment with HCQ did not modify the level of anti-ds-DNA in SLE (110 ± 9 ng/mL). In conclusion, chronic HCQ treatment reduced cardiac and renal hypertrophy, aortic endothelial dysfunction, and urinary protein excretion in severe SLE mice, despite the persistent elevation of anti-dsDNA, suggesting the involvement of new additional mechanisms to improve cardiovascular complications. Yildirim-Toruner et al., (2011). J Allergy Clin Immnunol 127:303-12. Supported by SAF2010-22066 and Ministerio de Ciencia e Innovación Campus de Excelencia Internacional (Programa GREIB)
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