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 efficientlydegraded by cysteine proteases or cathepsins. Dyslipemic status in insulin resistance and combinedhyperlipoproteinemia diseases include raised levels of very low density lipoproteins (VLDL), triglyceride(TG)-cholesteryl ester (CE)-rich lipoproteins. Enhanced VLDL concentration promotes cardiomyocyteintracellular cholesteryl ester (CE) accumulation in a LRP1-dependent manner. The aim of this work wasto analyze the effect of cardiomyocyte intracellular CE accumulation on tropoelastin (TE) characteristicsand to investigate the role of LRP1 and cathepsin S (CatS) on these effects. Molecular studies showed thatLRP1 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 showedthat LRP1-mediated intracellular CE accumulation increased CatS mature protein levels and induced analtered intracellular TE globule structure. Biophysical studies evidenced that LRP1-mediated intracellularCE accumulation caused a significant drop of Tg2 glass transition temperature of cardiomyocyte secretedTE. Moreover, CatS deficiency prevented the alterations in TE intracellular globule structure and on TEglass transition temperature. These results demonstrate that LRP1-mediated cardiomyocyte intracellularCE accumulation alters the structural and physical characteristics of secreted TE through an increase inCatS mature protein levels. Therefore, the modulation of LRP1-mediated intracellular CE accumulation incardiomyocytes could impact pathological ventricular remodeling associated with insulin-resistance andcombined hyperlipoproteinemia, pathologies characterized by enhanced concentrations of TG-CE-richlipoproteins.