MiRNA signature related to atherosclerotic lesion induced shear stress modifications in familial hypercholesterolemia patients with subclinical atherosclerosis: a bioinformatics systems biology study

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Institute of Health Carlos III (ISCIII) Background Patients with familial hypercholesterolemia (FH), even when appropriately treated, are at risk of premature clinical atherosclerotic cardiovascular disease (ASCVD) presentation. Although atherosclerosis (AT) is directly related to hemodynamic disturbances affecting the vascular geometry, there is scarce information on whether there is miRNA-mediated/flow-mediated modulation of atherosclerosis in FH. Purpose To identify a differential plasma miRNA signature related to fluid shear stress (FSS) in well controlled FH-patients with asymptomatic atherosclerosis. Methods FH-patients (N=49) with subclinical atherosclerosis, identified by computed tomographic angiography, and a reference cohort of non-FH subjects (N=32), both from a national FH-Registry, were included in the study. Coronary plaque volume and phenotype was analyzed by means of the QAngio CT imaging system. miRNAs associated to FSS were defined in silico by bioinformatics (KEGG, Cytoscape, GTEX portal, miRWalk, miRBase tools) and validated in plasma samples by RT-qPCR using TaqMan technology. Results By in silico analysis, 7 miRNAs targeting genes involved in features of functions (ROS production, oxidative stress, leukocyte transendothelial/migration-inflammation and vasodilation) of shear stress-induced cellular dysfunction and atherosclerosis (KEGG, hsa05418) were identified by miRWalk and miRBase databases. Of the 7 miRNAs, a 6-miRNA signature showed significantly lower plasma levels in FH-patients than in the non-FH group (P<0.01 for: miR-30e-5p, miR-378a-3p, let-7d-3p, and miR-550-5p; P=0.03 for miR-324-3p). In the FH-group, miR-324-3p, miR-30e-5p, miR-378a-3p and let-7d-3p significantly discriminated patients stratified by the plaque volume of non-calcified lesions (fibro-lipidic phenotype), using the median plaque volume as cut-off value. And even further, a high percentage (65-70%) of FH-subjects with low levels of the 4 miRNA had plaque volumes above the median. Interestingly, this miRNA-signature did not differentiate FH-patients stratified by the volume of calcified plaques. Conclusion FH-patients show a significantly lower content of an atherosclerosis/shear stress signature of 4 miRNAs targeting genes involved in subclinical atherosclerosis progression in FH.