Role of miR‐15a‐5p and miR‐199a‐3p in the inflammatory pathway regulated by NF‐κB in experimental and human atherosclerosis

• Published in: Clinical and translational medicine 2023-08, Vol.13 (8), p.e1363-n/a
• Main Authors: González‐López, Paula, Álvarez‐Villarreal, Marta, Ruiz‐Simón, Rubén, López‐Pastor, Andrea R., Ceniga, Melina Vega, Esparza, Leticia, Martín‐Ventura, José L., Escribano, Óscar, Gómez‐Hernández, Almudena
• Format: Article
• Language: English
• Subjects: Atherosclerosis; Biomarkers; Chemokines; Clinical medicine; Coronary vessels; Heart attacks; Inflammation; Laboratory animals; MicroRNAs; miRNAs; NF‐κB; Plasma; Transcription factors
• ISSN: 2001-1326; 2001-1326
• DOI: 10.1002/ctm2.1363

Background Cardiovascular diseases (CVDs) prevalence has significantly increased in the last decade and atherosclerosis development is the main trigger. MicroRNAs (miRNAs) are non‐coding RNAs that negatively regulate gene expression 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 and miR‐199a‐3p levels in aorta from apolipoprotein knockout (ApoE−/−) mice, an experimental model of hyperlipidemia‐induced atherosclerosis, and in human aortic and carotid atherosclerotic samples. By in silico studies, Western blot analysis and immunofluorescence studies, we detected the targets of the altered miRNAs. Results Our results show that miR‐15a‐5p and miR‐199a‐3p are significantly decreased in carotid and aortic samples from patients and mice with atherosclerosis. In addition, we found an increased expression in targets of both miRNAs that participate in the inflammatory pathway of nuclear factor kappa B (NF‐κB), such as IKKα, IKKβ and p65. In human vein endothelial cells (HUVECs) and vascular smooth muscle cells (VSMCs), the overexpression of miR‐15a‐5p or miR‐199a‐3p decreased IKKα, IKKβ and p65 protein levels as well as NF‐κB activation. On the other hand, miR‐15a‐5p and miR‐199a‐3p overexpression reduced ox‐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 analyses for miR‐15a‐5p, the area under the curve was 0.8951 with a p value 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 be involved in the NF‐κB activation pathway, as well as in ox‐LDL uptake by VSMCs, contributing to inflammation and progression atherosclerosis. Finally, miR‐15a‐5p could be used as a novel diagnostic biomarker for advanced atherosclerosis. This study demonstrates a novel role for miR‐15a‐5p and miR‐199a‐3p in atherosclerosis progression. Both miRNAs have an anti‐inflammatory role due to the regulation of their targets involved NF‐kappa B pathway, in addition, they have an anti‐foaming role in vascular smooth muscle cells. Finally, miR‐15a‐5p might be useful for diagnosis of advanced carotid atherosclerosis.