title: Hypoxia worsens the impact of intracellular triglyceride accumulation promoted by electronegative low-density lipoprotein in cardiomyocytes by impairing perilipin 5 upregulation.
abstract: Plasma lipoproteins are a source of lipids for the heart, and the proportion of electronegative low density lipoprotein [LDL(-)] is elevated in cardiometabolic diseases. Perilipin 5 (Plin5) is a crucial protein for lipid droplet management in the heart. Our aim was to assess the effect of LDL(-) on intracellular lipid content and Plin5 levels in cardiomyocytes and to determine whether these effects were influenced by hypoxia. HL-1 cardiomyocytes were exposed to native LDL [LDL(+)], LDL(-), and LDL(+) enriched in non-esterified fatty acids (NEFA) by phospholipase A2 (PLA2)-mediated lipolysis [PLA2-LDL(+)] or by NEFA loading [NEFA-LDL(+)] under normoxia or hypoxia. LDL(-), PLA2-LDL(+) and NEFA-LDL(+) raised the intracellular NEFA and triglyceride (TG) content of normoxic cardiomyocytes. Plin5 was moderately upregulated by LDL(+) but more highly upregulated by LDL(-), PLA2-LDL(+) and NEFA-LDL(+) in normoxic cardiomyocytes. Hypoxia enhanced the effect of LDL(-), PLA2-LDL(+) and NEFA-LDL(+) on intracellular TG and NEFA concentrations but, in contrast, counteracted the upregulatory effect of these LDLs on Plin5. Fluorescence microscopy experiments showed that hypoxic cardiomyocytes exposed to LDL(-), PLA2-LDL(+) and NEFA-LDL(+) have an increased production of reactive oxygen species (ROS). By treating hypoxic cardiomyocytes with WY-14643 (PPARα agonist), Plin5 remained high. In this situation, LDL(-) failed to enhance intracellular NEFA concentration and ROS production. In conclusion, these results show that Plin5 deficiency in hypoxic cardiomyocytes exposed to LDL(-) dramatically increases the levels of unpacked NEFA and ROS.
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, 08036 Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Revuelta-López
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, 08036 Barcelona, Spain.
authors.forename: Roi
authors.initials: R
authors.lastname: Cal
authors.affiliation: Metabolic Basis of Cardiovascular Risk, Institut d'Investigació de l'Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08036 Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Julve
authors.affiliation: Cardiovascular Biochemistry Group, Institut d'Investigació de l'Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08036 Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Rull
authors.affiliation: Cardiovascular Biochemistry Group, Institut d'Investigació de l'Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08036 Barcelona, Spain; Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Campus de Bellaterra, Cerdanyola, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Martínez-Bujidos
authors.affiliation: Cardiovascular Biochemistry Group, Institut d'Investigació de l'Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08036 Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Perez-Cuellar
authors.affiliation: Cardiovascular Biochemistry Group, Institut d'Investigació de l'Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08036 Barcelona, Spain; Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Campus de Bellaterra, Cerdanyola, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Ordoñez-Llanos
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, 08036 Barcelona, Spain.
authors.forename: Lina
authors.initials: L
authors.lastname: Badimon
authors.affiliation: Cardiovascular Biochemistry Group, Institut d'Investigació de l'Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08036 Barcelona, Spain. Electronic address: jsanchezq@santpau.cat.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Sanchez-Quesada
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, 08036 Barcelona, Spain. Electronic address: cllorente@csic-iccc.org.
authors.forename: Vicenta
authors.initials: V
authors.lastname: Llorente-Cortés
mesh_terms: D000818:Animals; D009202:Cardiomyopathies; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D005230:Fatty Acids, Nonesterified; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D005230:Fatty Acids, Nonesterified; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; D009124:Muscle Proteins; D014280:Triglycerides; C551268:lipid storage droplet protein 5, mouse; C099252:oxidized low density lipoprotein
keywords: Cardiomyopathy; Electronegative LDL; HL-1 cardiomyocytes; Nonesterified fatty acids; Perilipin 5