Background Atherosclerosis (AT) and cardiovascular disease (CVD) are enhanced in autoimmune diseases, such as antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). Characterization of the molecular and cellular basis of signalling abnormalities within the immune system that lead to auto reactivity and inflammation and their relationship to early AT and CVD development remain critical for understanding the pathogenesis of APS and SLE. Although there is evidence that statins have anti-inflammatory properties, their mechanism of action remains incompletely understood.
Objectives i) To determine if the proinflammatory SLE profile is related to their oxidative status, and associated to the autoimmune condition and the clinical disease activity;
ii) to test the anti-inflammatory effectiveness of fluvastatin.
Methods The study was conducted in 64 SLE patients and 47 healthy donors. Flow cytometry, ELISA and enzymatic assays were used to evaluate markers of inflammation and oxidative stress in white blood cells and plasma. Carotid-intimate media thickness (CIMT) was used as surrogate parameter of AT. Microarray expression profiling was used in paired samples of SLE monocytes from 21 patients before and after one month of in vivo fluvastatin treatment. Real-Time RT-PCR of selected genes was used to validate microarray data.
Results Increased TF and PAR2 levels were found in monocytes from SLE patients, which also displayed higher plasma levels of VEGF, IL8, MCP-1, TNFαand tPA. SLE monocytes displayed a decreased mitochondrial membrane potential (MMP) and increased levels of peroxides, GSH, and antioxidant enzymes (SOD2, catalase and GPx). aPL-IgG and anti-dsDNA levels significantly correlated with SLEDAI, markers of inflammation, thrombosis and oxidative stress. CIMT was associated to increased aPL-IgG, TF, VEGF and tPA, as well as to decreased MMP. The occurrence of cardiovascular events was associated with reduced MMP and SOD2, and increased catalase and GPx activity, as well as with increased levels of inflammatory markers. A total of 726 genes displayed significant changes in expression after 1 month of fluvastatin treatment, of which 30% were found associated to CVD. Fluvastatin treatment led to downregulation of many genes related to inflammation, angiogenesis and the atherosclerosis pathways. Genes related to mitochondrial activity, NO, and oxidative stress signalling pathways were also found significantly altered. The expression changes in selected cytokines, associated intracellular pathways, and markers of oxidative stress were further confirmed at protein level.
Conclusions i) SLE-related auto-antibodies significantly contribute to the development of AT and CVD. ii) A redox-sensitive pathway (in which mitochondrial membrane alterations seem to perform a main part) might play a key role in the elicitation of those pathologies in the setting of SLE. iii) Fluvastatin has significant anti-inflammatory effects on SLE monocytes, downregulating the expression of molecules
mediating angiogenesis, AT and inflammatory signalling. Supported by JA0246/2009, P08CVI04234 and PS09/01809.
Disclosure of Interest None Declared
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