Dagli-Hernandez Carolina, Freitas Renata Caroline Costa de, Luchessi Andre Ducati, Hirata Thiago Dominguez Crespo, Fajardo Cristina Moreno, Borges Jessica Bassani, Oliveira Victor Fernandes de, Rosa Neta Antonia Pereira, Faludi Andre Arpad, Gonçalves Rodrigo Marques, Bortolin Raul Hernandes, Malaquias Vanessa Barbosa, Bastos Gisele Medeiros, Sampaio Marcelo Ferraz, Hirata Mario Hiroyuki, Hirata Rosario Dominguez Crespo
Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil; Department of Pharmacy, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil; Department of Cardiac Surgery, Boston Children's Hospital, Boston, Massachusetts.
J Pharmacol Exp Ther. 2025 Jul;392(7):103626. doi: 10.1016/j.jpet.2025.103626. Epub 2025 Jun 7.
MicroRNAs (miRNAs) contribute to the variability in statin response by modulating genes involved in lipid metabolism. However, no studies evaluating exosomal miRNA profiles after statin treatment in patients with familial hypercholesterolemia (FH) have been performed. This study aimed to explore the effects of short-term statin treatment on the miRNA profile of plasma exosomes from patients with FH. Thirty-eight patients with FH on 6-week statin treatment and 32 normolipidemic subjects (control group) were selected. Plasma exosomes were isolated, and miRNA expression was analyzed by small RNA sequencing. Enrichment analysis was used to identify miRNA targets, interactions, and pathways. Expression of let-7a, miR-16, miR-92a, miR-122, and miR-486a was higher in the FH group than in the control group (fold change, ≥±1.5; P < .05). Statin treatment upregulated miR-92a and downregulated let-7b and miR-423 (P < .05) in plasma exosomes from patients with FH. In the overall group, baseline levels (normalized counts) of let-7a, miR-16, miR-92a, miR-122, and miR-486 were positively correlated with total and low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B and inversely correlated with high-density lipoprotein cholesterol (P < .05). Let-7b and miR-423 were also correlated with total cholesterol and triglycerides. The FH- and statin-dysregulated miRNAs target genes involved in cell cycle and proliferation, protein catabolism, and other biological processes, in addition to cholesterol homeostasis and cardiovascular function. In conclusion, FH and statin treatment alter the profile of plasma exosome-derived miRNAs, which have potential application as biomarkers for FH assessment and statin treatment monitoring. Future studies with larger cohorts, extended treatment periods, and validation via quantitative polymerase chain reaction are warranted to elucidate the role of these miRNAs in FH and statin response. SIGNIFICANCE STATEMENT: This study describes the effects of short-term statin treatment on circulating microRNAs (miRNAs) expression in familial hypercholesterolemia (FH). Five miRNAs were upregulated in plasma exosomes from patients with FH compared with healthy subjects. Six-week statin treatment upregulated miR-92a and downregulated miR-423 and let-7b in patients with FH. These miRNAs target genes with multiple biological functions and possible involvement in FH pathogenesis and statin response, making them potential candidates as biomarkers for therapy monitoring.
微小RNA（miRNA）通过调节参与脂质代谢的基因，导致他汀类药物反应的变异性。然而，尚未有研究评估家族性高胆固醇血症（FH）患者接受他汀类药物治疗后的外泌体miRNA谱。本研究旨在探讨短期他汀类药物治疗对FH患者血浆外泌体miRNA谱的影响。选取了38例接受6周他汀类药物治疗的FH患者和32例血脂正常的受试者（对照组）。分离血浆外泌体，并通过小RNA测序分析miRNA表达。采用富集分析来鉴定miRNA的靶标、相互作用和通路。FH组中let-7a、miR-16、miR-92a、miR-122和miR-486a的表达高于对照组（倍数变化≥±1.5；P<0.05）。他汀类药物治疗使FH患者血浆外泌体中的miR-92a上调，let-7b和miR-423下调（P<0.05）。在总体组中，let-7a、miR-16、miR-92a、miR-122和miR-486的基线水平（标准化计数）与总胆固醇、低密度脂蛋白胆固醇、甘油三酯和载脂蛋白B呈正相关，与高密度脂蛋白胆固醇呈负相关（P<0.05）。let-7b和miR-423也与总胆固醇和甘油三酯相关。除了胆固醇稳态和心血管功能外，FH和他汀类药物失调的miRNA靶向参与细胞周期和增殖、蛋白质分解代谢及其他生物学过程的基因。总之，FH和他汀类药物治疗改变了血浆外泌体来源的miRNA谱，这些miRNA具有作为FH评估和他汀类药物治疗监测生物标志物的潜在应用价值。有必要进行更大样本量、更长治疗周期并通过定量聚合酶链反应进行验证的未来研究，以阐明这些miRNA在FH和他汀类药物反应中的作用。重要声明：本研究描述了短期他汀类药物治疗对家族性高胆固醇血症（FH）患者循环微小RNA（miRNA）表达的影响。与健康受试者相比，FH患者血浆外泌体中有5种miRNA上调。6周的他汀类药物治疗使FH患者的miR-92a上调，miR-423和let-7b下调。这些miRNA靶向具有多种生物学功能的基因，可能参与FH发病机制和他汀类药物反应，使其成为治疗监测生物标志物的潜在候选者。
