LDL oxidation, oxysterol formation and endothelial cell
dysfunction
Cholesterol is the most abundant lipid in eukaryotic cells where it is
an important component of membranes. It is synthesized within the cells
in the endoplasmic reticulum, although this organelle contains only
0.5-5% of the total cell cholesterol (Iuliano, 2011; Lange et
al ., 1999). LDL are the main carriers of cholesterol and, as such, are
important contributors to atherosclerotic lesion progression. Indeed,
under physiological conditions, LDL penetrate the intima via
transcytosis across EC, but this process is further stimulated by EC
dysfunction. Subendothelial accumulation and retention of LDL is an
early step in atherogenesis. Skalen and coworkers (2002) demonstrated
that the extracellular matrix, mainly consisting of proteoglycans, plays
a key role in the retention of LDL. On the other hand, oxidative
modification of LDL prevents their interaction with proteoglycans and
favors their uptake by macrophages through scavenger receptors, leading
to cholesterol accumulation and foam cell formation (Öörni et
al., 1997).
The oxidation of LDL is thought to mainly occur in the extracellular
matrix underlying the arterial wall because in circulation they are
protected by plasma antioxidants (Carmena et al ., 1996). Multiple
mechanisms mediated by transition metals and enzymes are involved in LDL
oxidation. However, at now, the physiological in vivo relevant
mechanism is still not clear (Yoshida and Kisugi, 2010). Most of the
cells present in the arterial intima can promote LDL oxidation in
vitro by its enzymes, and ROS seem to play an active role. For example,
high LDL levels and shear stress can enhance EC-mediated hydrogen
peroxide (H2O2) production (Zouaoui
Boudjeltia et al ., 2004). A relevant mechanism leading to
oxidation of LDL occurs via myeloperoxidase (MPO) secreted by
activated phagocytes. This enzyme generates oxLDL by producing
hypochlorous acid (HOCl) from H2O2 and
chloride. Zhang and coworker (2013) speculated that MPO could use the
NADPH-derived H2O2 in order to produce
HOCl, thus promoting the oxidation of LDL.
Oxidized LDL are particularly rich in oxysterols which are 27-atom
carbon compounds formed after enzymatic or non-enzymatic cholesterol
oxidation in vivo . However, oxysterols can also be derived from
the diet. The methods of processing, preparation and storage expose the
food to air, light or heat leading to the formation of oxysterols
(Lordan et al ., 2009). Oxysterols circulate in the blood stream
in both free and esterified forms, carried by lipoproteins.
Interestingly, it has been demonstrated that the incorporation of
oxysterols into LDL particles makes LDL more susceptible to oxidation
(Vine et al ., 1998; Staprans et al ., 2003).
Oxysterols are involved in many physiological processes such as
cholesterol metabolism, hormone and vitamin D synthesis, and
transmembrane signaling as components of membrane microdomains enriched
in cholesterol (lipid rafts and caveolae). On the other hand,
accumulation of these compounds in tissues and organs has been
associated with the progression of several diseases, such as
atherosclerosis, neurodegenerative diseases, and cancer (Poli et
al ., 2013; Voisin et al ., 2017). A growing body of evidence
suggests that oxysterols and oxLDL play a key role in endothelial
dysfunction impairing the formation/production of NO, increasing the
formation of ROS and promoting the release of pro-inflammatory cytokines
(Lubrano and Balzan, 2014; Maiolino et al ., 2013). Furthermore,
it has been observed that oxysterols are able to remodel the endothelial
layer by inducing endothelial dysfunction followed by cell death
(Luchetti et al ., 2019; Luchetti et al ., 2015).