LRP1 immunotherapy enhances cardiomyocyte respiration by restricting cholesteryl ester accumulation in mitochondria
Por:
Benitez-Amaro, A, Garcia, E, Lhoëst, MTL, Polishchuk, A, Zegri-Reiriz, I, Vilades, D, Guerra, JM, Fernández-del-Rio, L, Mirabet, S, Samouillan, V, Shirihai, O, Liesa, M, Enrich, C, Llorente-Cortés, V
Publicada:
1 may 2025
Ahead of Print:
1 abr 2025
Resumen:
Antibodies (Abs) targeting the P3 sequence (Gly1127-Cys1140) of LDL receptor-related protein 1 (anti-P3 Abs) inhibit the interaction between ApoB100 in cholesteryl ester (CE)-enriched lipoproteins and the CR9 domain in LDL receptor-related protein 1, preventing intracellular CE accumulation induced by a high-fat high-cholesterol (HFHC) diet in cardiomyocytes. This study examines (i) whether HFHC induces cholesterol accumulation in mitochondria, and impacts cardiac bioenergetics, and (ii) the effectiveness of anti-P3 Abs in mitigating HFHC-induced mitochondrial alterations. Cardiac tissue was homogenized, and mitochondria were isolated through subcellular fractionation. Thin layer chromatography demonstrated that HFHC induced the accumulation of CE in cardiac mitochondria, and that this process was significantly reduced by anti-P3 Abs. In line, transmission electron microscopy studies revealed that morphological changes induced by HFHC in cardiomyocyte mitochondria were reversed, at least in part, by anti-P3 Abs. Additionally, anti-P3 Abs promoted more extensive interactions between mitochondria and lipid droplets (LDs), accompanied by an increase in LD diameter and electrodensity in cardiomyocytes. Cardiac mitochondrial respiratory capacity assessed by Seahorse analysis showed that HFHC reduced CI/CIV and CII/CIV activity ratios, while anti-P3 Abs restored complex II/IV activity. In conclusion, by blocking CE uptake from lipoproteins, anti-P3 Abs reduce CE accumulation in the cardiomyocyte mitochondria and LDs, enhance bioenergetically favorable mitochondria/LD interactions, and improve cardiomyocyte respiratory function in hypercholesterolemic rabbits. These findings highlight the therapeutic potential of anti-P3 Abs in metabolic diseases by limiting CE loading of mitochondria and LDs in the heart and restoring cardiac bioenergetics.
Filiaciones:
Benitez-Amaro, A:
CSIC, Biomed Res Inst Barcelona, Lipids & Cardiovasc Pathol Grp, IIBB, Barcelona, Spain
Inst Recerca Sant Pau IR SANt PAU, Barcelona, Spain
Garcia, E:
CSIC, Biomed Res Inst Barcelona, Lipids & Cardiovasc Pathol Grp, IIBB, Barcelona, Spain
Inst Recerca Sant Pau IR SANt PAU, Barcelona, Spain
Univ Autonoma Barcelona, Dept Med, Barcelona, Spain
Lhoëst, MTL:
CSIC, Biomed Res Inst Barcelona, Lipids & Cardiovasc Pathol Grp, IIBB, Barcelona, Spain
Inst Recerca Sant Pau IR SANt PAU, Barcelona, Spain
Univ Autonoma Barcelona, Dept Bioquim & Biol Mol, Barcelona, Spain
Polishchuk, A:
CSIC, Biomed Res Inst Barcelona, Lipids & Cardiovasc Pathol Grp, IIBB, Barcelona, Spain
Inst Recerca Sant Pau IR SANt PAU, Barcelona, Spain
Zegri-Reiriz, I:
Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Inst Recerca Sant Pau IR SANT PAU, Dept Cardiol, Barcelona, Spain
Vilades, D:
Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Inst Recerca Sant Pau IR SANT PAU, Dept Cardiol, Barcelona, Spain
Inst Hlth Carlos III, CIBERCV, Madrid, Spain
Guerra, JM:
Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Inst Recerca Sant Pau IR SANT PAU, Dept Cardiol, Barcelona, Spain
Inst Hlth Carlos III, CIBERCV, Madrid, Spain
Fernández-del-Rio, L:
Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA USA
Univ Calif Los Angeles, David Geffen Sch Med, Metab Theme, Los Angeles, CA USA
Mirabet, S:
Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Inst Recerca Sant Pau IR SANT PAU, Dept Cardiol, Barcelona, Spain
Inst Hlth Carlos III, CIBERCV, Madrid, Spain
Samouillan, V:
Univ Paul Sabatier, Univ Toulouse, Equipe PHYPOL, CIRIMAT, Toulouse, France
Shirihai, O:
Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA USA
Univ Calif Los Angeles, David Geffen Sch Med, Metab Theme, Los Angeles, CA USA
Liesa, M:
CSIC, Inst Biol Mol Barcelona, IBMB, Barcelona, Spain
CIBERDEM Inst Hlth Carlos III, Madrid, Spain
Enrich, C:
Univ Barcelona, Dept Biomed, Unitat Biol Cellular, Fac Med & Ciencies Salut, Barcelona, Spain
Inst Invest Biomed August Pi i Sunyer IDIBAPS, Ctr Recerca Biomed CELLEX, Barcelona, Spain
Llorente-Cortés, V:
CSIC, Biomed Res Inst Barcelona, Lipids & Cardiovasc Pathol Grp, IIBB, Barcelona, Spain
Inst Recerca Sant Pau IR SANt PAU, Barcelona, Spain
Inst Hlth Carlos III, CIBERCV, Madrid, Spain
Green Submitted, gold
|