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de Freitas, Renata Caroline Costa ; Bortolin, Raul Hernandes ; Kuraoka, Shiori ; Rogers, Maximillian A. ; Blaser, Mark C. ; Chelvanambi, Sarvesh ; Borges, Jessica Bassani ; de Oliveira, Victor Fernandes ; Dagli-Hernandez, Carolina ; Bastos, Gisele Medeiros ; Marcal, Elisangela da Silva Rodrigues ; Malaquias, Vanessa Barbosa ; Goncalves, Rodrigo Marques ; Faludi, Andre Arpad ; Silbiger, Vivian Nogueira ; Luchessi, Andre Ducati ; Aikawa, Masanori ; Hirata, Rosario Dominguez Crespo ; Singh, Sasha A. ; Aikawa, Elena ; Hirata, Mario Hiroyuki

• Tipo de documento: Artigo Científico
• Fonte: Clinica Chimica Acta; v. 568, p. 13-pg., 2025-01-11.

Resumo

Background and aims: Familial Hypercholesterolemia (FH) is a monogenic disease that leads to early-onset atherosclerosis. Causative mutations in FH-related genes are found in 60-80 % of patients, while epigenetic factors may contribute to mutation-negative cases. This study analyzed miRNAs and proteins from plasmaderived extracellular vesicles (EVs) of FH patients to explore their contribution in FH diagnosis. Methods: Clinical and laboratory data were obtained from 54 FH patients and 38 normolipidemic individuals. FHrelated gene variants were identified using exon-targeted gene sequencing. Plasma EVs miRNome and proteome were analysed using small RNA sequencing and liquid chromatography/mass spectrometry. Results: Thirteen FH patients carried LDLR deleterious variants (MD group), while 41 did not (non-MD group). Over 2000 miRNAs were detected in plasma EVs, with miR-122-5p higher in FH patients compared to controls, and miR-21-5p higher in the MD group than in the non-MD group (p < 0.05). Proteomic analysis identified 300 proteins with 18 out of 38 proteins more abundant in EVs than in total plasma. Eighteen EVs-derived proteins had differential abundance in FH patients compared to control group (p < 0.05). EV levels of miR-122-5p, miR21-5p and 12 proteins were correlated with serum lipids (p < 0.05). The integrative analysis between dysregulated miRNAs (miR-122-5p and miR-21-5p) and altered proteins (APOD, APOF, MBL2 and MASP1) from EVs identified several common pathways involved in cholesterol metabolism. Conclusion: Co-regulation of plasma EVs miR-122-5p, miR-21-5p, APOD, APOF, MBL2 and MASP1 and their correlation with serum lipids suggest their involvement in impaired cholesterol metabolism and may be useful as biomarkers of FH severity. (AU)

• Processo FAPESP: 16/12899-6 - Caracterização genômica, epigenômica e farmacogenômica de portadores de hipercolesterolemia familial na população brasileira
• Beneficiário: Mario Hiroyuki Hirata
• Modalidade de apoio: Auxílio à Pesquisa - Temático