Author + information
- Received January 18, 2017
- Revision received April 21, 2017
- Accepted May 3, 2017
- Published online July 3, 2017.
- Teresa Padró, PhDa,b,c,
- Judit Cubedo, PhDa,b,c,
- Sandra Camino, PhDa,b,
- Maria Teresa Béjar, PhDa,b,
- Soumaya Ben-Aicha, MSa,b,
- Guiomar Mendieta, MDa,d,
- Joan Carles Escolà-Gil, PhDb,e,
- Rafael Escate, PhDa,b,
- Manuel Gutiérrez, MDa,b,
- Laura Casani, PhDa,b,
- Lina Badimon, PhDa,b,c,f and
- Gemma Vilahur, PhDa,b,c,∗ ()
- aCardiovascular Science Institute - ICCC, Barcelona, Spain
- bInstitut d’Investigacions Biomèdiques, IIB-Sant Pau, Barcelona, Spain
- cCentro de Investigación Biomédica en Red Cardiovascular (CIBERCV) Instituto de Salud Carlos III, Barcelona, Spain
- dDepartment of Cardiology, Hospital Clinic, Barcelona, Spain
- eCentro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) Hospitalet de Llobregat, Barcelona, Spain
- fCardiovascular Research Chair, Universidad Autónoma Barcelona (UAB), Barcelona, Spain
- ↵∗Address for correspondence:
Dr. Gemma Vilahur, Cardiovascular Science Institute, c/Sant Antoni Ma Claret 167, 08025 Barcelona, Spain.
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.
This work was supported by Plan Nacional de Salud (SAF2015-71653-R to Dr. Vilahur and SAF2016-76819R to Dr. Badimon) from the Spanish Ministry of Science and Innovation; a grant from the Spanish Society of Cardiology (Beca FEC Investigación Básica 2016 to Dr. Vilahur); CIBERCV (to Dr. Badimon); CIBERDEM (to Dr. Escolà-Gil); Fundació La Marató de TV3 (105/U/2015 to TP and 155/U/2015 to GV); FIS (PI16/01915 to Dr. Padró and PI16/00139 to Dr. Escolà-Gil); from Instituto de Salud Carlos III; FEDER Una Manera de Hacer Europa; and a grant from the Muy Ilustrísima Administración from the Hospital de la Santa Creu I Sant Pau (to Dr. Gutiérrez). The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Badimon and Vilahur contributed equally to this work. Philip Barter, MBBS, PhD, served as Guest Editor for this paper.
- Received January 18, 2017.
- Revision received April 21, 2017.
- Accepted May 3, 2017.
- 2017 American College of Cardiology Foundation