Detrimental Effect of Hypercholesterolemia on High-Density Lipoprotein Particle Remodeling in Pigs
Por:
Padró T., Cubedo J., Camino S., Béjar M.T., Ben-Aicha S., Mendieta G., Escolà-Gil J.C., Escate R., Gutiérrez M., Casani L., Badimon L., Vilahur G.
Publicada:
1 ene 2017
Resumen:
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. © 2017 American College of Cardiology Foundation
Filiaciones:
Padró T.:
Cardiovascular Science Institute - ICCC, Barcelona, Spain
Institut d'Investigacions Biomèdiques, IIB-Sant Pau, Barcelona, Spain
Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV) Instituto de Salud Carlos III, Barcelona, Spain
Cubedo J.:
Cardiovascular Science Institute - ICCC, Barcelona, Spain
Institut d'Investigacions Biomèdiques, IIB-Sant Pau, Barcelona, Spain
Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV) Instituto de Salud Carlos III, Barcelona, Spain
Camino S.:
Cardiovascular Science Institute - ICCC, Barcelona, Spain
Institut d'Investigacions Biomèdiques, IIB-Sant Pau, Barcelona, Spain
Béjar M.T.:
Cardiovascular Science Institute - ICCC, Barcelona, Spain
Institut d'Investigacions Biomèdiques, IIB-Sant Pau, Barcelona, Spain
Ben-Aicha S.:
Cardiovascular Science Institute - ICCC, Barcelona, Spain
Institut d'Investigacions Biomèdiques, IIB-Sant Pau, Barcelona, Spain
Mendieta G.:
Cardiovascular Science Institute - ICCC, Barcelona, Spain
Department of Cardiology, Hospital Clinic, Barcelona, Spain
Escolà-Gil J.C.:
Institut d'Investigacions Biomèdiques, IIB-Sant Pau, Barcelona, Spain
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) Hospitalet de Llobregat, Barcelona, Spain
Escate R.:
Cardiovascular Science Institute - ICCC, Barcelona, Spain
Institut d'Investigacions Biomèdiques, IIB-Sant Pau, Barcelona, Spain
Gutiérrez M.:
Cardiovascular Science Institute - ICCC, Barcelona, Spain
Institut d'Investigacions Biomèdiques, IIB-Sant Pau, Barcelona, Spain
Casani L.:
Cardiovascular Science Institute - ICCC, Barcelona, Spain
Institut d'Investigacions Biomèdiques, IIB-Sant Pau, Barcelona, Spain
Badimon L.:
Cardiovascular Science Institute - ICCC, Barcelona, Spain
Institut d'Investigacions Biomèdiques, IIB-Sant Pau, Barcelona, Spain
Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV) Instituto de Salud Carlos III, Barcelona, Spain
Cardiovascular Research Chair, Universidad Autónoma Barcelona (UAB), Barcelona, Spain
Vilahur G.:
Cardiovascular Science Institute - ICCC, Barcelona, Spain
Institut d'Investigacions Biomèdiques, IIB-Sant Pau, Barcelona, Spain
Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV) Instituto de Salud Carlos III, Barcelona, Spain
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