Role of miR‐15a‐5p and miR‐199a‐3p in the inflammatory pathway regulated by NF‐κB in experimental and human atherosclerosis
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2023
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Wiley
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González‐López P, Álvarez‐Villarreal M, Ruiz‐Simón R, López‐Pastor AR, De Ceniga MV, Esparza L, et al. Role of miR‐15a‐5p and miR‐199a‐3p in the inflammatory pathway regulated by NF‐κB in experimental and human atherosclerosis. Clinical & Translational Med 2023;13:e1363. https://doi.org/10.1002/ctm2.1363.
Abstract
Background: Cardiovascular diseases (CVDs) prevalence has significantlyincreased in the last decade and atherosclerosis development is the main trig-ger. MicroRNAs (miRNAs) are non-coding RNAs that negatively regulate geneexpression of their target and their levels are frequently altered in CVDs.
Methods: By RT-qPCR, we analysed miR-9-5p, miR-15a-5p, miR-16-5p andmiR-199a-3p levels in aorta from apolipoprotein knockout (ApoE−/−) mice, anexperimental model of hyperlipidemia-induced atherosclerosis, and in humanaortic and carotid atherosclerotic samples. By in silico studies, Western blotanalysis and immunofluorescence studies, we detected the targets of the alteredmiRNAs.
Results: Our results show that miR-15a-5p and miR-199a-3p are significantlydecreased in carotid and aortic samples from patients and mice with atheroscle-rosis. In addition, we found an increased expression in targets of both miRNAsthat participate in the inflammatory pathway of nuclear factor kappa B (NF-κB), such as IKKα,IKKβand p65. In human vein endothelial cells (HUVECs)and vascular smooth muscle cells (VSMCs), the overexpression of miR-15a-5p ormiR-199a-3p decreased IKKα,IKKβand p65 protein levels as well as NF-κB acti-vation. On the other hand, miR-15a-5p and miR-199a-3p overexpression reducedox-LDL uptake and the inflammation regulated by NF-κB in VSMCs. Moreover,although miR-15a-5p and miR-199a-3p were significantly increased in exosomes from patients with advanced carotid atherosclerosis, only in the ROC analysesfor miR-15a-5p, the area under the curve was 0.8951 with apvalue of .0028.
Conclusions: Our results suggest that the decrease of miR-199a-3p and miR-15a-5p in vascular samples from human and experimental atherosclerosis could beinvolvedintheNF-κBactivationpathway,aswellasinox-LDLuptakebyVSMCs,contributing to inflammation and progression atherosclerosis. Finally, miR-15a-5p could be used as a novel diagnostic biomarker for advanced atherosclerosis.