Potential protective role of let-7d-5p in atherosclerosis progression reducing the inflammatory pathway regulated by NF-κB and vascular smooth muscle cells proliferation

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1870; no. 7; p. 167327
• Main Authors: Aroca-Esteban, Javier, Souza-Neto, Francisco V., Aguilar-Latorre, Carlota, Tribaldo-Torralbo, Alba, González-López, Paula, Ruiz-Simón, Rubén, Álvarez-Villareal, Marta, Ballesteros, Sandra, de Ceniga, Melina Vega, Landete, Pedro, González-Rodríguez, Águeda, Martín-Ventura, José L., de las Heras, Natalia, Escribano, Óscar, Gómez-Hernández, Almudena
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2024
• Subjects: Aged; Atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; Biomarker; Biomarkers - metabolism; Carotid Artery Diseases - genetics; Carotid Artery Diseases - metabolism; Carotid Artery Diseases - pathology; Cell Proliferation; Disease Progression; Extracellular Vesicles - metabolism; Extracellular Vesicles - pathology; Female; Humans; Inflammation; Inflammation - metabolism; Inflammation - pathology; Male; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; miRNAs; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; NF-kappa B - metabolism; Signal Transduction; VSMCs; Biomarker; miRNAs; O.C.T; CAD; IKK; AKT; Inflammation; ORO; IκBα; NF-κB; TNF-α; Atherosclerosis; FAs; miRNA; CVDs; CA; ACA
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167327

The prevalence of cardiovascular diseases (CVDs) is increasing in the last decades, even is the main cause of death in first world countries being atherosclerosis one of the principal triggers. Therefore, there is an urgent need to decipher the underlying mechanisms involved in atherosclerosis progression. In this respect, microRNAs dysregulation is frequently involved in the progression of multiple diseases including CVDs. Our aim was to demonstrate that let-7d-5p unbalance could contribute to the pathophysiology of atherosclerosis and serve as a potential diagnostic biomarker. We evaluated let-7d-5p levels in vascular biopsies and exosome-enriched extracellular vesicles (EVs) from patients with carotid atherosclerosis and healthy donors. Moreover, we overexpressed let-7d-5p in vitro in vascular smooth muscle cells (VSMCs) to decipher the targets and the underlying mechanisms regulated by let-7d-5p in atherosclerosis. Our results demonstrate that let-7d-5p was significantly upregulated in carotid plaques from overweight patients with carotid atherosclerosis. Moreover, in EVs isolated from plasma, we found that let-7d-5p levels were increased in carotid atherosclerosis patients compared to control subjects specially in overweight patients. Receiver Operating Characteristic (ROC) analyses confirmed its utility as a diagnostic biomarker for atherosclerosis. In VSMCs, we demonstrated that increased let-7d-5p levels impairs cell proliferation and could serve as a protective mechanism against inflammation by impairing NF-κB pathway without affecting insulin resistance. In summary, our results highlight the role of let-7d-5p as a potential therapeutic target for atherosclerosis since its overexpression induce a decrease in inflammation and VSMCs proliferation, and also, as a novel non-invasive diagnostic biomarker for atherosclerosis in overweight patients. Protective role of let-7d-5p in atherosclerosis. The levels of let-7d-5p were significantly increased in carotid from overweight patients with advanced atherosclerosis (ACA) and in overweight patients with MeS and carotid atherosclerosis (CA). The increase of this miRNA provokes a significant decrease of its potential target expression IKKβ, as well as its phosphorylation. As a consequence, VSMCs maintain higher IκBα levels and reduced NF-κB activation, contributing to the protection against the inflammation present in atherosclerosis. On the other hand, let-7d-5p overexpression also produced a significant reduction of IR, IGF-IR, AKT and mTOR, diminishing p42/44 MAPK activation without modify AKT and p70S6K activation. On the other hand, let-7d-5p also might have an atheroprotective role due to the reduction of VSMCs proliferation induced by TNF-α or PA. Finally, we isolated miRNAs from EVs (enriched in exosomes) of patients with advanced atherosclerosis and healthy controls as well as MeS patients with or without CA and a significant increase of let-7d-5p in EVs from ACA and CA was noted, therefore, this miRNA might be useful as a non-invasive biomarker of advanced atherosclerosis and in overweight patients with MeS and CA. [Display omitted] •Vascular and circulating let-7d-5p is increased in overweight patients with atherosclerosis.•Increased let-7d-5p reduces inflammation in atherosclerosis by decreasing NF-κB.•Circulating let-7d-5p is a potential biomarker for advanced atherosclerosis.