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19b and miR-124, both of them critical players in the expression of proteins related to inflammation and throm- bosis in APS and SLE.8,9
Correlation studies revealed that the altered circulating miRNA signature in APS is linked to parameters related to increased risk of peripheral artery disease such as ABI. Moreover, correlations between circulating miRNA levels and numerous altered parameters related to inflammation and thrombosis were also identified. These correlations support the relationship observed in the in silico study between the selected miRNAs and potential target pro- teins involved in various clinical features of APS. The influence of the autoimmunity in the circulating profile of miRNAs in APS was also revealed by the significant corre- lation between high titers of aPL-IgG and the altered expression of several miRNAs integrating the signature. These relationships further sustain those previously iden- tified among the altered profile of miRNAs in APS and SLE at cellular level and the autoimmune and inflammatory profile of both autoimmune conditions.9 Therefore, our data suggest that the altered plasma profile of miRNAs is an important mechanisin that might contribute to the reg- ulation of the pro-atherothrombotic status of APS patients, on which aPL seem to play a key role.
Our in vitro studies further confirmed this hypothesis, demonstrating that aPL-IgG antibodies promoted a signif- icant deregulation in the expression levels of both the selected miRNAs and their potential protein targets in the supernatant of cultured monocytes and HUVECs, the main drivers of the CVD in the setting of APS. These results also confirm and complement previous studies which showed the in vitro effects of aPL-IgG in the induc- tion of prothrombotic/inflammatory mediators3,31 and the modulation of specific cellular miRNAs involved in their modulation.8,9 Nevertheless, although our data show spe- cific effects of aPL-IgG on the secretion of several circulat- ing microRNAs related to CVD, the contribution of other components of the vascular and immune system to the altered profile of circulating miRNAs still has to be
defined. In addition, since we did not perform a complete plasma human microarray analysis, we cannot exclude the complementary role of other circulating miRNAs in the physiopathology of APS.
Interestingly, our analysis supports a clinical role for the use of miRNA ratios when stratifying patients for their thrombotic risk. While studying the miRNA expression profile has widened the understanding of APS pathogene- sis,9 its clinical utility is still a question of debate. Our data support the view that specific miRNA signatures could identify subgroups of APS patients showing different clin- ical profiles (in terms of site of thrombosis and risk of recurrences), potentially paving the way for their use as useful biomarkers that will increase the specificity and sensitivity of thrombotic risk assessment.
Taken together, our data suggest that differentially expressed miRNAs in the plasma of APS patients, modu- lated at least partially by aPL-IgG antibodies, might have the potential to serve as novel biomarkers of disease fea- tures and could help typify the atherothrombotic status of patients, thus constituting a useful tool in the manage- ment of this disease.
Acknowledgments
We thank all patients for their participation in this study.
Funding
This study was supported by grants from the Junta de Andalucia (CTS-7940), the Instituto de Salud Carlos III (ref. n. PI15/01333), Cofinanciado por el Fondo Europeo de Desarrollo Regional de la Unión Europea 'Una manera de hacer Europa', Spain, and the Spanish Inflammatory and Rheumatic Diseases Network (RIER), Instituto de Salud Carlos III (RD16/0012/0015). CL-P was supported by a contract from the Spanish Junta de Andalucía. YJ-G was supported by a contract from the University of Cordoba (Co-financing of the Research Plan of the University of Cordoba and the Operating Program of the European Regional Development Funds -ERDF- for Andalusia).
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