The interplay between oxLDL and caveolae/caveolin and their
impact on endothelial dysfunction
Uptake and transcytosis of circulating oxLDL, together with oxidation of
LDL in the subendothelium, play an important role in the development of
atherosclerosis. As for LDL, these processes seem to involve
caveolae-mediated mechanisms. Transcytosis of oxLDL via caveolae
was suggested by Sun et al . (2010) who showed that two caveolae
specific inhibitors, filipin and nocodazole, decrease the uptake of
oxLDL by human umbilical vein endothelial cells (HUVEC). The lectin-like
oxidized LDL receptor 1 (LOX-1) is the major receptor for binding,
internalization and degradation of oxLDL in EC, and LOX-1 expression is
up-regulated by oxLDL (Sawamura et al ., 1997; Li and Mehta, 2000)
(Figure 2). Interestingly, also Cav-1 expression is up-regulated by
oxLDL, while Cav-1 silencing results in decreased LOX-1 expression upon
oxLDL administration, suggesting that caveolin participates in LOX-1
regulation. It is known that the binding of oxLDL to LOX-1 stimulates
the development of atherosclerosis through different mechanisms
involving: i) activation of MAPK proteins, which causes increased
expression of adhesion molecules and chemoattractants; ii) stimulation
of NADPH oxidase activity, leading to ROS production, oxidative stress,
and consequent reduction of NO levels; and iii) activation of NF-kB
signaling pathway, resulting in cytokine and adhesion molecule
production as well as increased expression of LOX-1 itself, thus
creating a vicious cycle of proinflammatory signaling (Kattoor et
al ., 2019) (Figure 2).
More recently, the possible role of LOX-1 in oxLDL transcytosis has been
questioned by Huang et al. (2019) who demonstrated that knockdown
of LOX-1 did not alter the uptake of oxLDL in human aortic endothelial
cells (HAEC). By contrast, a decrease in oxLDL transfer was observed
when the expression of SR-B1 was downregulated, thus suggesting that
transcytosis of oxLDL in EC occurs via the SR-B1 receptor rather than
LOX-1 (Huang et al ., 2019) (Figure 2).
Further investigations are necessary to clarify the molecular pathways
responsible for oxLDL uptake and transcytosis and the role of caveolin
in these processes.
Caveolae are enriched in free cholesterol and changes in the content of
this lipid can affect the morphology and signaling mediated by caveolae.
To this regard, Smart et al . (1994) described for the first time
that cholesterol oxidation results in the translocation of caveolin from
plasma membrane to Golgi with a modest reduction in the number of
caveolae. Later, Blair et al. (1999) were able to show that oxLDL
can indeed deplete caveolar cholesterol and induce the transfer of Cav-1
and eNOS to intracellular compartments, thus enabling NO production
(Figure 2).
The mechanism through which oxLDL may deplete cholesterol is unknown. It
has been hypothesized that oxLDL may act as a cholesterol acceptor to
remove cholesterol from cellular membranes rather than loading cells
with cholesterol. A higher efflux of cholesterol induced by oxLDL has
also been proposed, in a mechanism that involves the binding of oxLDL to
CD36 receptors. Finally, a redistribution of cholesterol between
membrane-rich and cholesterol-poor domains has been proposed (Shentuet al ., 2010). Even though the effects of oxLDL on membrane
cholesterol remain elusive and controversial, the effects of oxLDL on EC
function impairment are very similar to those observed after
experimental-induced cholesterol depletion, suggesting a common
mechanism of action (Levitan and Shentu, 2011).
Zhu and coworkers (2005) demonstrated that oxLDL can inhibit the
transcription of ATP-binding cassette transporter-1 (ABCA1) in HUVEC
cells. This transporter mediates the active efflux of cholesterol and/or
phospholipids. The regulation of ABAC1 by oxLDL occurs at the
transcriptional level through the inhibition of endogenous LXR ligand
production. The role of caveolin in cholesterol homeostasis is less
understood. Overexpression of Cav-1 up-regulated ABCA1 expression and
enhanced cholesterol efflux to extracellular effectors (Lin et
al ., 2007). Conversely, Cav-1 knock down was associated with reduced
free cholesterol and increased esterified cholesterol, but it had
minimal effects on cellular cholesterol efflux (Frank et al .,
2006). Whether oxLDL might affect cholesterol homeostasis by directly
interfering with Cav-1 levels is not known. It is well established that
Cav-1 is regulated by cellular cholesterol levels (Bist et al .,
1997). In line with these observations, caveolin mRNA levels were found
up-regulated by free cholesterol, but down-regulated by oxysterols in
fibroblast monolayers (Fielding et al ., 1997).
Finally, an exchange in free cholesterol between plasma LDL particles
and the luminal surface of EC is supposed to occur (Stender, 1982). In
this context, oxLDL have been shown to induce an increase in endothelial
stiffness by direct incorporation of oxysterols into the endothelial
plasma membrane (Figure 2) (Shentu et al ., 2012). It has been
hypothesized that this event could result in the disruption of the
structure of lipid-ordered domains, including caveolae. Moreover, there
is evidence that oxysterols interact with Cav-1 (Sleer et al .,
2001). These direct oxysterol effects might produce relevant
consequences on caveolae-mediated signaling.
Thus, although the molecular mechanisms through which oxLDL lead to
endothelial dysfunction must be still clarified, accumulating evidence
point to a relevant role of direct/indirect disruption of cholesterol
homeostasis/distribution which may in turn affect caveolae function and
modulate signaling pathways relevant for the development of
atherosclerosis.