The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a scavenger receptor responsible for ox-LDL recognition, binding and internalization, which is up-regulated during atherogenesis. Its activation triggers endothelium dysfunction and induces inflammation. A soluble form of LOX-1 has been identified in the human blood and its presence considered a biomarker of cardiovascular diseases. We recently showed that cholesterol-lowering drugs inhibit ox-LDL binding and internalization, rescuing the ox-LDL induced apoptotic phenotype in primary endothelial cells. Here we have investigated the molecular bases of human LOX-1 shedding by metalloproteinases and the role of cell membrane cholesterol on the regulation of this event by modulating its level with MβCD and statins. We report that membrane cholesterol affects the release of different forms of LOX-1 in cells transiently and stably expressing human LOX-1 and in a human endothelial cell line (EA.hy926). In particular, our data show that i) cholesterol depletion triggers the release of LOX-1 in exosomes as a full-length transmembrane isoform and as a truncated ectodomain soluble fragment (sLOX-1); ii) endothelial cells secrete a soluble metalloproteinase which induces LOX-1 ectodomain shedding and iii) long term statins treatment enhances sLOX-1 proteolytic shedding.

Gioia, M., Vindigni, G., Testa, B., Raniolo, S., Fasciglione, G., Coletta, M., et al. (2015). Membrane cholesterol modulates LOX-1 shedding in endothelial cells. PLOS ONE, 10(10), e0141270 [10.1371/journal.pone.0141270].

Membrane cholesterol modulates LOX-1 shedding in endothelial cells

GIOIA, MAGDA;COLETTA, MASSIMILIANO;BIOCCA, SILVIA
2015

Abstract

The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a scavenger receptor responsible for ox-LDL recognition, binding and internalization, which is up-regulated during atherogenesis. Its activation triggers endothelium dysfunction and induces inflammation. A soluble form of LOX-1 has been identified in the human blood and its presence considered a biomarker of cardiovascular diseases. We recently showed that cholesterol-lowering drugs inhibit ox-LDL binding and internalization, rescuing the ox-LDL induced apoptotic phenotype in primary endothelial cells. Here we have investigated the molecular bases of human LOX-1 shedding by metalloproteinases and the role of cell membrane cholesterol on the regulation of this event by modulating its level with MβCD and statins. We report that membrane cholesterol affects the release of different forms of LOX-1 in cells transiently and stably expressing human LOX-1 and in a human endothelial cell line (EA.hy926). In particular, our data show that i) cholesterol depletion triggers the release of LOX-1 in exosomes as a full-length transmembrane isoform and as a truncated ectodomain soluble fragment (sLOX-1); ii) endothelial cells secrete a soluble metalloproteinase which induces LOX-1 ectodomain shedding and iii) long term statins treatment enhances sLOX-1 proteolytic shedding.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/12
Settore BIO/10
English
Con Impact Factor ISI
Gioia, M., Vindigni, G., Testa, B., Raniolo, S., Fasciglione, G., Coletta, M., et al. (2015). Membrane cholesterol modulates LOX-1 shedding in endothelial cells. PLOS ONE, 10(10), e0141270 [10.1371/journal.pone.0141270].
Gioia, M; Vindigni, G; Testa, B; Raniolo, S; Fasciglione, G; Coletta, M; Biocca, S
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/127465
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