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Title

Detrimental effect of hypercholesterolemia on high-density lipoprotein particle remodeling in pigs

AuthorsPadró Capmany, Teresa; Cubedo Ràfols, Judit; Camino, Sandra; Béjar, Maria Teresa; Ben-Aicha, Soumaya; Mendieta, Guiomar; Escolà-Gil, Joan Carles; Escate, Rafael; Gutiérrez, Manuel; Casaní, Laura; Badimón Maestro, Lina; Vilahur, Gemma
KeywordsCardioprotection
Cholesteryl ester
Fatty acid
Lipidomics
Proteomics
Issue Date11-Jul-2017
PublisherElsevier
CitationJournal of the American College of Cardiology 70(2): 165-178 (2017)
Abstract[Background] Beneficial effects of high-density lipoproteins (HDL) seem altered in patients with symptomatic cardiovascular disease. We recently demonstrated in a swine model of ischemia-reperfusion (IR) that hypercholesterolemia abolishes HDL-related cardioprotection. [Objectives] This study sought to investigate, using the same animal model, whether the reported impairment of HDL cardioprotective function was associated with alterations in HDL remodeling and functionality. [Methods] Pigs were fed a normocholesterolemic (NC) or hypercholesterolemic (HL) diet for 10 days, reaching non-HDL cholesterol concentrations of 38.2 ± 3.5 mg/dl and 218.6 ± 27.6 mg/dl, respectively (p < 0.0001). HDLs were isolated, and lipidomics and differential proteomics tests were performed to determine HDL molecular changes. HDL functionality and particle size were determined. [Results] Using principal component analysis, we identified 255 molecular lipid species differentially clustered in NC-HDL and HL-HDL. Ninety lipid metabolites were differentially expressed, and 50 showed at least 1.5-fold variation (false discovery rate adjustment q value <0.05). HL-HDLs presented a core enriched in cholesteryl esters and a surface depleted of phosphatidylcholine species containing polyunsaturated and long-chain fatty acids, indicating the presence of mature HDL particles with low surface fluidity. Hypercholesterolemia induced an important change in HDL-transported proteins (576 spots in HL-HDL vs. 621 spots in NC-HDL). HL-HDLs showed a reduced content of lipocalin retinol binding protein 4 and apolipoprotein M and in the retinoic acid-transporter cellular retinoic acid binding protein 1 (p < 0.05 vs. NC-HDL). No changes were observed in apolipoprotein A-I content and profile. Functionally, HL-HDL showed lower antioxidant activity (−35%) and a reduced capacity to efflux cholesterol (−60%) compared to NC-HDL (p < 0.05). Hypercholesterolemia induced larger HDL particles. [Conclusions] We demonstrate that hypercholesterolemia induces HDL lipidomic changes, losing phosphatidylcholine-lipid species and gaining cholesteryl esters, and proteomic changes, with losses in cardioprotective proteins. These remodeling changes shifted HDL particles toward a dysfunctional state.
Publisher version (URL)https://doi.org/10.1016/j.jacc.2017.05.018
URIhttp://hdl.handle.net/10261/176812
DOIhttp://dx.doi.org/10.1016/j.jacc.2017.05.018
ISSN1558-3597
Appears in Collections:(IIBB) Artículos
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