High-density lipoprotein remodelled in hypercholesterolaemic blood induce epigenetically driven down-regulation of endothelial HIF-1α expression in a preclinical animal model

Abstract

Aims 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). Methods and results 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). Conclusion 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.

Advances in HDL: Much More than Lipid Transporters

“…As such, an association between HDL-miRNAs profile and CAD stability has been established [97], and the content of HDL-miR-223 is found to be altered in the presence of insulin resistance and familial hypercholesterolemia subjects [26,[98][99][100][101][102]. Extending these previous findings, we have recently evidenced that hypercholesterolemic HDL particles transport higher levels of miR-126 as compared to native-HDL, which in turn is delivered to endothelial cells through an SRB1-dependent mechanism likely modulating HIF-1α expression [103].…”

Plasma exosome-derived microRNAs expression profiling and bioinformatics analysis under cross-talk between increased low-density lipoprotein cholesterol level and ATP-sensitive potassium channels variant rs1799858

“…Besides the LDL-C, the miR-221/222 family was also associated with low HDL-C phenotype [ 15 ]. Similar to the association of miR-221/222 family with dyslipidemia (LDL-C/HDL-C), this phenomenon was also seen on miR-126-5p [ 16 , 17 ]. In addition, miR-490-3p [ 18 ], miR-320b [ 19 ], miR-210-3p [ 20 ], miR-17-3p [ 21 ] and miR-33a-5p [ 22 ] were linked to LDL-C metabolism while miR-22-3p [ 23 ], miR-31-5p [ 24 ], miR-378b [ 25 ], and miR-135a-3p [ 26 ] were linked to HDL-C metabolism.…”

RNAs on the Go: Extracellular Transfer in Insects with Promising Prospects for Pest Management

“…Furthermore, miRNA-delivery mediated by HDL was shown to be dependent on scavenger receptor class B type I [ 185 ]. Since then, other reports have emphasized the role of HDLs in intercellular RNA transfer, as well as the potential use of these lipoproteins as therapeutic-delivery vehicles [ 185 , 186 , 187 , 188 , 189 , 190 , 191 ]. Interestingly, insect and other arthropod lipoproteins were demonstrated to adhere to dsRNA, suggesting a potential role of these proteins in mediating RNA-based communication in this phylum [ 169 , 192 , 193 ] ( Figure 1 ).…”