Atherosclerosis and cardiovascular disease in systemic lupus erythematosus: effects of in vivo statin treatment
Atherosclerosis and cardiovascular disease in systemic lupus erythematosus: effects of in vivo statin treatment
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系统性红斑狼疮的动脉粥样硬化和心血管疾病：他汀类药物体内治疗的效果
DOI：
10.1136/annrheumdis-2013-204351
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发表时间：
2014
影响因子：
27.4
通讯作者：
C. López
中科院分区：
文献类型：
--
作者：
P. Ruiz;N. Barbarroja;C. Pérez;M. Aguirre;M. Bertolaccini;M. Khamashta;A. Rodríguez;Y. Almadén;P. Seguí;Husam Khraiwesh;J. González;J. M. Villalba;E. Collantes;M. Cuadrado;C. López
目的他汀类药物除降胆固醇作用外，可能对系统性红斑狼疮（SLE）的血管有有益作用，但其作用机制尚不完全清楚。我们研究了氟伐他汀预防SLE动脉粥样硬化血栓形成的潜在机制。方法选择85例SLE患者和62例健康献血员。选定的患者（n=27）接受20 mg/天的氟伐他汀1个月。 在治疗开始前和治疗结束时采集血样。来自5名患者的单核细胞在体外用氟伐他汀处理。结果系统性红斑狼疮患者的血栓前状态和炎症指标增加。SLE单核细胞显示线粒体膜电位改变和氧化应激增加。相关性和关联性分析表明，SLE患者自身免疫、氧化应激、炎症和动脉粥样硬化血栓形成风险增加之间存在复杂的相互作用。氟伐他汀治疗1个月的患者减少了SLE疾病活动指数和脂质水平，氧化状态和血管炎症。对单核细胞的阵列研究表明氟伐他汀治疗后799个基因的差异表达。氟伐他汀调控的新靶基因和途径被发现，包括涉及胆固醇和脂质代谢、炎症、氧化应激和线粒体活性的基因网络。电子显微镜分析显示，氟伐他汀治疗患者的单核细胞中线粒体密度体积增加，这些患者还显示出参与线粒体生物合成的基因表达更高。SLE单核细胞的体外处理证实了体内研究中获得的结果。结论：我们的总体数据表明，氟伐他汀改善了参与SLE动脉粥样硬化血栓形成病理生理过程的氧化还原敏感性通路的损伤。
Objective Statins may have beneficial vascular effects in systemic lupus erythematosus (SLE) beyond their cholesterol-lowering action, although the mechanisms involved are not completely understood. We investigated potential mechanisms involved in the efficacy of fluvastatin in preventing atherothrombosis in SLE. Methods Eighty-five patients with SLE and 62 healthy donors were included in the study. Selected patients (n=27) received 20 mg/day fluvastatin for 1 month. Blood samples were obtained before the start and at the end of treatment. Monocytes from five patients were treated in vitro with fluvastatin. Results Increased prothrombotic and inflammatory variables were found in patients with SLE. SLE monocytes displayed altered mitochondrial membrane potential and increased oxidative stress. Correlation and association analyses demonstrated a complex interplay among autoimmunity, oxidative stress, inflammation and increased risk of atherothrombosis in SLE. Fluvastatin treatment of patients for 1 month reduced the SLE Disease Activity Index and lipid levels, oxidative status and vascular inflammation. Array studies on monocytes demonstrated differential expression in 799 genes after fluvastatin treatment. Novel target genes and pathways modulated by fluvastatin were uncovered, including gene networks involved in cholesterol and lipid metabolism, inflammation, oxidative stress and mitochondrial activity. Electron microscopy analysis showed increased density volume of mitochondria in monocytes from fluvastatin-treated patients, who also displayed higher expression of genes involved in mitochondrial biogenesis. In vitro treatment of SLE monocytes confirmed the results obtained in the in vivo study. Conclusions Our overall data suggest that fluvastatin improves the impairment of a redox-sensitive pathway involved in processes that collectively orchestrate the pathophysiology of atherothrombosis in SLE.