RNY-derived small RNAs as a signature of coronary artery disease

BMC Medicine

Michele Trabucchi⁶  Laurent O. Martinez⁷  Pascal Barbry³  Jean Ferrières⁷  Raymond Ruimy²  Romain Lotte²  Annelise Genoux⁷  Laura Bouchareychas⁵  Bertrand Perret⁷  Laure-Emmanuelle Zaragosi³  Jean-Bernard Ruidavets⁴  Mohamed Benahmed⁸  Nedra Tekaya⁶  Zoheir Hizir⁶  Laeticia Lichtenstein¹  Emanuela Repetto⁶ 

[1] Université de Toulouse III, UMR 1048, Toulouse 31300, France;Hôpital Archet, Nice, France;CNRS and University of Nice Sophia Antipolis, IPMC, Sophia Antipolis, Nice, France;INSERM U1027, Faculté de Médecine, Toulouse 31073, France;Sorbonne Universités, UPMC Université Paris 06, UMR_S 1166, ICAN, Integrative Biology of Atherosclerosis Team, Paris F-75005, France;INSERM U1065 and University of Nice Sophia Antipolis, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 10 “Control of Gene Expression”, Nice, F-06204, France;CHU de Toulouse, Hôpital Purpan, Toulouse, France;INSERM U1065, Team 5, Nice, F-06204, France

关键词: Small RNA;    Macrophage;    Coronary artery disease;    Biomarker;    Atherosclerosis;   

Others  :  1229151
DOI  :  10.1186/s12916-015-0489-y

 received in 2015-08-07, accepted in 2015-09-16,  发布年份 2015

【 摘 要 】

Background

Data from next generation sequencing technologies uncovered the existence of many classes of small RNAs. Recent studies reported that small RNAs are released by cells and can be detected in the blood. In this report, we aimed to discover the occurrence of novel circulating small RNAs in coronary artery disease (CAD).

Methods

We used high-throughput sequencing of small RNAs from human and mouse apoptotic primary macrophages, and analyzed the data by empirical Bayes moderated t-statistics to assess differential expression and the Benjamini and Hochberg method to control the false discovery rate. Results were then confirmed by Northern blot and RT-qPCR in foam cells and in two animal models for atherosclerosis, namely ApoE ^−/− and Ldlr ^−/− mouse lines. Quantitative RT-PCR to detect identified small RNAs, the RNY-derived small RNAs, was performed using sera of 263 patients with CAD compared to 514 matched healthy controls; the Student t-test was applied to statistically assess differences. Associations of small RNAs with clinical characteristics and biological markers were tested using Spearman’s rank correlations, while multivariate logistic regressions were performed to test the statistical association of small RNA levels with CAD.

Results

Here, we report that, in macrophages stimulated with pro-apoptotic or pro-atherogenic stimuli, the Ro-associated non-coding RNAs, called RNYs or Y-RNAs, are processed into small RNAs (~24–34 nt) referred to as small-RNYs (s-RNYs), including s-RNY1-5p processed from RNY1. A significant upregulation of s-RNY expression was found in aortic arches and blood plasma from ApoE ^−/− and Ldlr ^−/− mice and in serum from CAD patients (P <0.001). Biostatistical analysis revealed a positive association of s-RNY1-5p with hs-CRP and ApoB levels; however, no statistical interaction was found between either of these two markers and s-RNY1-5p in relation to the CAD status. Levels of s-RNY1-5p were also independent from statin and fibrate therapies.

Conclusion

Our results position the s-RNY1-5p as a relevant novel independent diagnostic biomarker for atherosclerosis-related diseases. Measurement of circulating s-RNY expression would be a valuable companion diagnostic to monitor foam cell apoptosis during atherosclerosis pathogenesis and to evaluate patient’s responsiveness to future therapeutic strategies aiming to attenuate apoptosis in foam cells in advanced atherosclerotic lesions.

【 授权许可】

   
2015 Repetto et al.

【 图 表 】

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