title: Low-density lipoprotein receptor-related protein 1 mediates hypoxia-induced very low density lipoprotein-cholesteryl ester uptake and accumulation in cardiomyocytes.
abstract: OBJECTIVE
  The myocardium accumulates intracellular lipids under ischaemic conditions, and myocardial fat deposition is closely associated with cardiac dysfunction. Our aims were to analyse the effect of hypoxia on low-density lipoprotein receptor-related protein 1 (LRP1) expression in neonatal rat ventricular myocytes (NRVM) and cardiac-derived HL-1 cells and the molecular mechanisms involved in this effect, to determine the role of LRP1 in the very low density lipoprotein (VLDL) uptake by hypoxic cardiomyocytes, and to study the effect of hypoxia on lipoprotein receptor expression and myocardial lipid profile in an in vivo porcine experimental model of acute myocardial infarction.
  
  
  RESULTS
  Thin-layer chromatography after lipid extraction showed that VLDL exposure leads to cholesteryl ester (CE) and triglyceride (TG) accumulation in a dose-dependent manner and that hypoxic conditions further increased VLDL-derived intracellular lipid accumulation in HL-1 cells. Knockdown of LRP1 through lentiviral-mediated interfering RNA specifically prevented hypoxia-induced VLDL-CE internalization in HL-1 cells and NRVM. Lipopolysaccharide (LPS)-induced LRP1 overexpression specifically increased VLDL-CE accumulation in NRVM. In addition, using double-radiolabelled [(3)H]CE-[(14)C]TG-VLDL, we found that LRP1 deficiency specifically prevented hypoxia-induced VLDL-[(3)H]CE uptake. Finally, in an in vivo porcine model of infarcted myocardium, ischaemic areas exhibited LRP1 protein up-regulation and intramyocardial CE overaccumulation.
  
  
  CONCLUSIONS
  Our results demonstrate that hypoxia increases LRP1 expression through HIF-1α and that LRP1 overexpression mediates hypoxia-induced VLDL-CE uptake and accumulation in cardiomyocytes.
authors.affiliation: Cardiovascular Research Center,  CSIC-ICCC, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Sant Antoni Mª Claret, 167, 08025 Barcelona,  Spain.
authors.forename: Roi
authors.initials: R
authors.lastname: Cal
authors.forename: José
authors.initials: J
authors.lastname: Castellano
authors.forename: Elena
authors.initials: E
authors.lastname: Revuelta-López
authors.forename: Rosa
authors.initials: R
authors.lastname: Aledo
authors.forename: Montse
authors.initials: M
authors.lastname: Barriga
authors.forename: Jordi
authors.initials: J
authors.lastname: Farré
authors.forename: Gemma
authors.initials: G
authors.lastname: Vilahur
authors.forename: Laura
authors.initials: L
authors.lastname: Nasarre
authors.forename: Leif
authors.initials: L
authors.lastname: Hove-Madsen
authors.forename: Lina
authors.initials: L
authors.lastname: Badimon
authors.forename: Vicenta
authors.initials: V
authors.lastname: Llorente-Cortés
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D002788:Cholesterol Esters / Q000235:genetics / Q000378:metabolism*; D015243:Cholesterol, VLDL / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D050356:Lipid Metabolism / Q000502:physiology; D008079:Lipoproteins, VLDL / Q000235:genetics / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D013552:Swine / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D002788:Cholesterol Esters; D015243:Cholesterol, VLDL; D008079:Lipoproteins, VLDL; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins