Teresa Padró1, Judit Cubedo1, Sandra Camino2, Maria Teresa Béjar2, Soumaya Ben-Aicha2, Guiomar Mendieta3, Joan Carles Escolà-Gil4, Rafael Escate2, Manuel Gutiérrez2, Laura Casani2, Lina Badimon5, Gemma Vilahur6. 1. 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. 2. Cardiovascular Science Institute - ICCC, Barcelona, Spain; Institut d'Investigacions Biomèdiques, IIB-Sant Pau, Barcelona, Spain. 3. Cardiovascular Science Institute - ICCC, Barcelona, Spain; Department of Cardiology, Hospital Clinic, Barcelona, Spain. 4. 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. 5. 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. 6. 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. Electronic address: gvilahur@csic-iccc.org.
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.
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.
Authors: José Tuñón; Lina Badimón; Marie-Luce Bochaton-Piallat; Bertrand Cariou; Mat J Daemen; Jesus Egido; Paul C Evans; Imo E Hoefer; Daniel F J Ketelhuth; Esther Lutgens; Christian M Matter; Claudia Monaco; Sabine Steffens; Erik Stroes; Cécile Vindis; Christian Weber; Magnus Bäck Journal: Cardiovasc Res Date: 2019-01-01 Impact factor: 10.787
Authors: Michelle Averill; Katya B Rubinow; Kevin Cain; Jake Wimberger; Ilona Babenko; Jessica O Becker; Karen E Foster-Schubert; David E Cummings; Andrew N Hoofnagle; Tomas Vaisar Journal: J Clin Lipidol Date: 2019-11-22 Impact factor: 4.766
Authors: Nicholas J Woudberg; Sarah Pedretti; Sandrine Lecour; Rainer Schulz; Nicolas Vuilleumier; Richard W James; Miguel A Frias Journal: Front Pharmacol Date: 2018-01-22 Impact factor: 5.810
Authors: Yuling Zhang; Scott M Gordon; Hang Xi; Seungbum Choi; Merlin Abner Paz; Runlu Sun; William Yang; Jason Saredy; Mohsin Khan; Alan Thomas Remaley; Jing-Feng Wang; Xiaofeng Yang; Hong Wang Journal: Redox Biol Date: 2019-05-17 Impact factor: 11.799