Journal Article

Low-density lipoprotein receptor-related protein 1 mediates hypoxia-induced very low density lipoprotein-cholesteryl ester uptake and accumulation in cardiomyocytes

Roi Cal, José Castellano, Elena Revuelta-López, Rosa Aledo, Montse Barriga, Jordi Farré, Gemma Vilahur, Laura Nasarre, Leif Hove-Madsen, Lina Badimon and Vicenta Llorente-Cortés

in Cardiovascular Research

Published on behalf of European Society of Cardiology

Volume 94, issue 3, pages 469-479
Published in print June 2012 | ISSN: 0008-6363
Published online March 2012 | e-ISSN: 1755-3245 | DOI: https://dx.doi.org/10.1093/cvr/cvs136
Low-density lipoprotein receptor-related protein 1 mediates hypoxia-induced very low density lipoprotein-cholesteryl ester uptake and accumulation in cardiomyocytes

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Aims

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.

Methods and 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 [3H]CE-[14C]TG-VLDL, we found that LRP1 deficiency specifically prevented hypoxia-induced VLDL-[3H]CE uptake. Finally, in an in vivo porcine model of infarcted myocardium, ischaemic areas exhibited LRP1 protein up-regulation and intramyocardial CE overaccumulation.

Conclusion

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.

Keywords: LRP1; Cardiomyocytes; Cholesteryl esters; Hypoxia; HIF-1α

Journal Article.  5532 words.  Illustrated.

Subjects: Cardiovascular Medicine

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