title: Cardiomyocyte intracellular cholesteryl ester accumulation promotes tropoelastin physical alteration and degradation: Role of LRP1 and cathepsin S.
abstract: Dyslipemia has a direct impact on cardiac remodeling by altering extracellular matrix (ECM) components. One of the main ECM components is elastin, a proteic three-dimensional network that can be efficiently degraded by cysteine proteases or cathepsins. Dyslipemic status in insulin resistance and combined hyperlipoproteinemia diseases include raised levels of very low density lipoproteins (VLDL), triglyceride (TG)-cholesteryl ester (CE)-rich lipoproteins. Enhanced VLDL concentration promotes cardiomyocyte intracellular cholesteryl ester (CE) accumulation in a LRP1-dependent manner. The aim of this work was to analyze the effect of cardiomyocyte intracellular CE accumulation on tropoelastin (TE) characteristics and to investigate the role of LRP1 and cathepsin S (CatS) on these effects. Molecular studies showed that LRP1 deficiency impaired CE selective uptake and accumulation from TG-CE-rich lipoproteins (VLDL+IDL) and CE-rich lipoproteins (aggregated LDL, agLDL). Biochemical and confocal microscopic studies showed that LRP1-mediated intracellular CE accumulation increased CatS mature protein levels and induced an altered intracellular TE globule structure. Biophysical studies evidenced that LRP1-mediated intracellular CE accumulation caused a significant drop of Tg2 glass transition temperature of cardiomyocyte secreted TE. Moreover, CatS deficiency prevented the alterations in TE intracellular globule structure and on TE glass transition temperature. These results demonstrate that LRP1-mediated cardiomyocyte intracellular CE accumulation alters the structural and physical characteristics of secreted TE through an increase in CatS mature protein levels. Therefore, the modulation of LRP1-mediated intracellular CE accumulation in cardiomyocytes could impact pathological ventricular remodeling associated with insulin-resistance and combined hyperlipoproteinemia, pathologies characterized by enhanced concentrations of TG-CE-rich lipoproteins.
authors.affiliation: Physique des Polymères, Institut Carnot, CIRIMAT UMR 5085, Université Paul Sabatier, Bat 3R1B2, 118 route de Narbonne, 31062 Toulouse Cedex 04, France. Electronic address: valerie.samouillan@univ-tlse3.fr.
authors.forename: Valerie
authors.initials: V
authors.lastname: Samouillan
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Revuelta-López
authors.affiliation: Physique des Polymères, Institut Carnot, CIRIMAT UMR 5085, Université Paul Sabatier, Bat 3R1B2, 118 route de Narbonne, 31062 Toulouse Cedex 04, France.
authors.forename: Jany
authors.initials: J
authors.lastname: Dandurand
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Nasarre
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain.
authors.forename: Lina
authors.initials: L
authors.lastname: Badimon
authors.affiliation: Physique des Polymères, Institut Carnot, CIRIMAT UMR 5085, Université Paul Sabatier, Bat 3R1B2, 118 route de Narbonne, 31062 Toulouse Cedex 04, France.
authors.forename: Colette
authors.initials: C
authors.lastname: Lacabanne
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain. Electronic address: cllorente@csic-iccc.org.
authors.forename: Vicenta
authors.initials: V
authors.lastname: Llorente-Cortés
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D059748:Proteolysis; D034622:RNA Interference; D011924:Rats, Zucker; D017550:Spectroscopy, Fourier Transform Infrared; D014280:Triglycerides / Q000378:metabolism; D014333:Tropoelastin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002788:Cholesterol Esters; D008079:Lipoproteins, VLDL; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C000717609:Tgm2 protein, rat; D014280:Triglycerides; D014333:Tropoelastin; D002784:Cholesterol; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D002403:Cathepsins; C028217:cathepsin S
keywords: Cardiac remodeling; Cardiomyocyte; Cathepsin S; Intracellular cholesterol esters; Tropoelastin; VLDL