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In the “response-to-retention” model, the accumulation of low-density lipoprotein
(LDL) within the arterial wall is the first step of atherogenesis. However, to access
the vascular wall, LDL that is circulating within the blood stream must pass the endothelium.
This inner lining of the blood vessels is composed of endothelial cells and forms
a barrier between the blood stream and the surrounding tissues. Earlier evidences
suggested that plasma proteins including lipoproteins are filtrated passively through
endothelial cells in a concentration- and size-dependent manner. However, the stoke
diameter of LDL (20–30 nm) is much larger that the gap-junctions between endothelial
cells (3–6 nm). As the result of loss of function experiments performed either in vitro or in vivo, it is increasingly accepted that LDL but also high-density lipoprotein (HDL) are
rather actively transported through endothelial cells [
]. The first protein shown to limit transendothelial LDL transport was caveolin 1
(cav1). As a scaffolding protein, cav1 is the major constituent of caveolae, which
are small invaginations of the plasma membrane that in addition to clathrin coated
pits form a classical entry route for vesicular trafficking. The limiting role of
cav1 in LDL transcytosis through endothelial cells was first suggested in 2003 by
Frank and colleagues who observed less atherosclerotic lesions in cav1−/−*apoe−/−double knockout mice compared to apoe−/− single knockout mice despite markedly pronounced hypercholesterolemia [
]. Later, Fernandez-Hernando and colleagues demonstrated that re-expression of cav1
in endothelial cells of cav1−/− mice enhanced LDL accumulation as well as formation of atherosclerotic lesions within
the aortic wall [
]. Finally, Ramirez et al. recently demonstrated that the absence of cav1 from the
endothelium of ldlr−/− mice significantly reduced atherogenesis by limiting both LDL transcytosis through
aortic endothelial cells and vascular inflammation [
(A) LDL binds to the scavenger receptor BI (SR-BI) and the activin A receptor like
type 1 (ALK1) and is internalized and transcytosed via caveolae. A fraction of LDL
binds to the LDL receptor (LDLR) before being degraded via clathrin-coated pit uptake.
(B) Tumor necrosis factor alpha (TNFα), serum amyloid A (SAA), interleukin 1beta (IL-1β)
and C reactive protein (CRP) activate the nuclear factor kappa B (NF-κB) and LRP3-inflammasome
pathways. Translocation of NF-κB subunit to the nucleus induces caveolin1 (cav1) and
cavin-1 transcription leading to increase LDL transcytosis through endothelial cells.
LRP3-inflammasome activation induces IL-1β secretion further increasing LDL transcytosis.
TNFα also induces the expression of LDLR but reduces the expression of SR-BI. (C)
High-glucose level inhibits the AMPK-MTOR-PIK3C3 pathway blocking the degradation
of cav1 and cavin-1, which leads to enhanced level of cav1 and cavin-1 and induces
LDL transport. Cas1: caspase 1. Image was created using BioRender.
