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| Home > Articles > Published articles > High-density lipoprotein remodelled in hypercholesterolaemic blood induce epigenetically driven down-regulation of endothelial HIF-1α expression in a preclinical animal model |
| Home > Articles > Published articles > High-density lipoprotein remodelled in hypercholesterolaemic blood induce epigenetically driven down-regulation of endothelial HIF-1α expression in a preclinical animal model |
(Institut d'Investigació Biomèdica Sant Pau) (Institut d'Investigació Biomèdica Sant Pau) (Institut d'Investigació Biomèdica Sant Pau) (Institut d'Investigació Biomèdica Sant Pau) (Institut d'Investigació Biomèdica Sant Pau) (Institut d'Investigació Biomèdica Sant Pau) (Institut d'Investigació Biomèdica Sant Pau) (Universitat Autònoma de Barcelona. Càtedra de Recerca Cardiovascular) (Institut d'Investigació Biomèdica Sant Pau)| Date: | 2019 |
| Abstract: | High-density lipoproteins (HDLs) are circulating micelles that transport proteins, lipids, and miRNAs. HDL-transported miRNAs (HDL-miRNAs) have lately received attention but their effects on vascular cells are not fully understood. Additionally, whether cardiovascular risk factors affect HDL-miRNAs levels and miRNA transfer to recipient cells remains equally poorly known. Here, we have investigated the changes induced by hypercholesterolaemia on HDL-miRNA levels and its effect on recipient endothelial cells (ECs). Pigs were kept on a high-fat diet (HC; n = 10) or a normocholesterolaemic chow (NC; n = 10) for 10 days reaching cholesterol levels of 321. 0 (229. 7-378. 5) mg/dL and 74. 0 (62. 5-80. 2) mg/dL, respectively. HDL particles were isolated, purified, and quantified. HDL-miRNA profiling (n = 149 miRNAs) of HC- and NC-HDLs was performed by multipanel qPCR. Cell cultures of porcine aortic ECs were used to determine whether HDL-miRNAs were delivered to ECs. Potential target genes modulated by miRNAs were identified by bioinformatics and candidate miRNAs were validated by molecular analysis. In vivo effects in the coronary arteries of normocholesterolaemic swine administered HC- or NC-HDLs were analysed. Among the HDL-miRNAs, four were found in different amounts in HC- and NC-HDL (P < 0. 05). miR-126-5p and -3p and miR-30b-5p (2. 7×, 1. 7×, and 1. 3×, respectively) were found in higher levels and miR-103a-3p and miR-let-7g-5p (−1. 6×, −1. 4×, respectively) in lower levels in HC-HDL. miR-126-5p and -3p were transferred from HC-HDL to EC (2. 5×; P < 0. 05), but not from NC-HDL, by a SRB1-mediated mechanism. Bioinformatics revealed that HIF1α was the miR-126 target gene with the highest predictive value, which was accordingly found to be markedly reduced in HC-HDL-treated ECs and in miR126 mimic transfected ECs. In vivo validation confirmed that HIF1α was diminished in the coronary endothelial layer of NC pigs administered HC-HDL vs. those administered NC-HDL (P < 0. 05). Hypercholesterolaemia induces changes in the miRNA content of HDL enhancing miR126 and its delivery to ECs with the consequent down-regulation of its target gene HIF1α. |
| Grants: | Ministerio de Ciencia e Innovación SAF2016-76819-R Ministerio de Ciencia e Innovación PGC2018-094025-B-I00 Instituto de Salud Carlos III P17/01321 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017-SGR-1480 |
| Note: | Altres ajuts: This work was supported by the Plan Nacional de Salud (PNS) from the Spanish Ministry of Science and Innovation and funds FEDER 'Una Manera de Hacer Europa'; a grant from the Spanish Society of Cardiology (Beca FEC Investigacio'n Ba'sica/2016 to G.V); the Instituto de Salud Carlos III (ISCIII); and CIBERCV (to L.B). We thank the support of the Generalitat of Catalunya (Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat,) and the Fundación Investigación Cardiovascular-Fundación Jesus Serra for their continuous support. |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Subject: | HDL ; Dyslipidaemia ; Translational research ; MiRNAs ; Endothelial cells |
| Published in: | Cardiovascular research, Vol. 116 (august 2019) , p. 1288-1299, ISSN 1755-3245 |
