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Effects of copper sulfate-oxidized or myeloperoxidase- modified LDL on lipid loading and programmed cell death in macrophages under hypoxia

Authors Vlaminck B, Calay D, Genin M, Sauvage A, Ninane N, Boudjeltia K, Raes M, Michiels C

Received 31 March 2014

Accepted for publication 16 July 2014

Published 23 September 2014 Volume 2014:2 Pages 153—169

DOI https://doi.org/10.2147/HP.S65242

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 4


Benoit Vlaminck,1 Damien Calay,1 Marie Genin,1 Aude Sauvage,1 Noelle Ninane,1 Karim Zouaoui Boudjeltia,2 Martine Raes,1 Carine Michiels1

1Laboratory of Biochemistry and Cellular Biology (URBC), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Namur, Belgium; 2Laboratory of Experimental Medicine (ULB 222 Unit), Universite Libre de Bruxelles, CHU de Charleroi, Charleroi, Belgium

Abstract: Atheromatous plaques contain heavily lipid-loaded macrophages that die, hence generating the necrotic core of these plaques. Since plaque instability and rupture is often correlated with a large necrotic core, it is important to understand the mechanisms underlying foam cell death. Furthermore, macrophages within the plaque are associated with hypoxic areas but little is known about the effect of low oxygen partial pressure on macrophage death. The aim of this work was to unravel macrophage death mechanisms induced by oxidized low-density lipoproteins (LDL) both under normoxia and hypoxia. Differentiated macrophages were incubated in the presence of native, copper sulfate-oxidized, or myeloperoxidase-modified LDL. The unfolded protein response, apoptosis, and autophagy were then investigated. The unfolded protein response and autophagy were triggered by myeloperoxidase-modified LDL and, to a larger extent, by copper sulfate-oxidized LDL. Electron microscopy observations showed that oxidized LDL induced excessive autophagy and apoptosis under normoxia, which were less marked under hypoxia. Myeloperoxidase-modified LDL were more toxic and induced a higher level of apoptosis. Hypoxia markedly decreased apoptosis and cell death, as marked by caspase activation. In conclusion, the cell death pathways induced by copper sulfate-oxidized and myeloperoxidase-modified LDL are different and are differentially modulated by hypoxia.

Keywords: Ox-LDL, myeloperoxidase, hypoxia, UPR, apoptosis, autophagy, macrophages

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