MiR-6821-5p and coronary calcification in familial hypercholesterolemia patients with subclinical atherosclerosis. (10th June 2022)

• Record Type: Journal Article
• Authors: Padro, T; Escate, R; Suades, R; Mata, P; Badimon, L
• Is Part Of: Cardiovascular research. Volume 118(2022)Supplement 1
• Publication Date: 2022-06-10
• Subjects: Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvac066.199
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Funding Acknowledgements: Type of funding sources: Public Institution(s). Main funding source(s): Agencia Estatal de Investigaciópn (AEI)" - Spanish Ministry of Economy Competitiveness of Science Agencia Estatal de Investigaciópn (AEI)" - Spanish Institute of Health Carlos III, ISCIII Background: Familial hypercholesterolemia (FH) is associated with premature atherosclerosis but FH patients have a highly variable risk of clinical atherosclerotic cardiovascular disease (ACVD) presentation. Preclinical atherosclerosis has been identified by imaging of coronary artery calcium (CAC); however, little is known of the molecular pathways involved in vascular calcification in FH. Circulating microRNAs are proven as a powerful epigenetic regulators of atherosclerosis development. Purpose: We have investigated the circulating microRNA signature of FH patients with CAC and asymptomatic atherosclerosis. Methods: Differential plasma miRNA profiling was performed by Affymetrix microarray technology (discovery studies) and RT-PCR using TaqMan technology (validation studies) in plasma of FH subjects (N=86) included in a multicentric nationwide cohort. FH-patients with and without coronary calcification (determined by Agatston score) by computed tomographic angiography imaging were investigated. Proof-of-concept validation studies were performed in cell culture of human coronary-derived vascular smooth muscle cells (hcVSMC) calcification analysis. Results: Using a non-targeted approach, a differential signature of 15 miRNA (all upregulated) was identified in FH-patients presenting subclinical atherosclerosis with calcified plaques (FH-CCS+, N=49, Agatston score >100) compared with FH-subjects without coronary calcification (FH-CCS-, N=37, Agatston score 0). After RT-PCR validation, 3 miRNAs (miR-193a-5p, miR-30e-5p and miR-6821-5p) were significantly upregulated in FH-CCS+ patients. ROC-analysis confirmed miR-6821-5p as the best miRNA for discriminating FH-patients with coronary calcification (AUC 0.70±0.06, P=0.003). High miR-6821-5p levels associated to older age (P=0.003) and high LDL burden (P=0.014), two established risk factors for calcification. In vitro studies showed miR-6821-5p up-regulation (P=0.018) in hcVSMC cultured under calcification conditions (high-phosphate medium) and expressing increased levels of calcification-related genes such as SPP1 (Secreted Phosphoprotein 1, osteopontin) and BMP2 (Bone Morphogenetic Protein 2) when compared with non-calcified hcVSMC. Conclusion: Up-regulated levels of miR-6821-5p are found in FH patient with CAC+ atherosclerotic plaques, as well as in calcified isolated human coronary smooth muscle cells that express the pro-calcification genes as osteopontin and BMP2. miR-6821-5p is involved in the development of calcification in the coronary arteries and in the development of atherosclerotic plaques.