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Page 4 of 15 Miura et al. Vessel Plus 2019;3:1 I http://dx.doi.org/10.20517/2574-1209.2018.69

DYSLIPIDEMIA AND ATHEROSCLEROSIS
Total Cho
Numerous epidemiology and clinical studies have demonstrated that dyslipidemia is a major risk factor for
atherosclerosis formation [2,21] . Hypercholesterolemia increases levels of cellular free Cho about 2- to 4-fold in
[31]
vascular ECs . As a result, a high level of free Cho in ECs induces changes in the plasma membrane Cho
content and the composition of lipid rafts, leading to altering membrane function and therefore affecting
[32]
cell function in SMCs . High levels of free Cho also increase reactive oxygen species generation via
various mechanisms [31,33] . Increased reactive oxygen species generation causes EC dysfunction in terms of
reducing nitric oxide bioavailability and uncoupling endothelial nitric oxide synthase (eNOS). In addition,
hypercholesterolemia activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, xanthine
[21]
oxidases and myeloperoxidases, resulting in reactive oxygen species generation . Hypercholesterolemia
also promotes the secretion of a proinflammatory cytokine such as tumor necrosis factor-α, interleukin-
[21]
1β, and interferon-γ, as well as mitochondrial and NADPH oxidase-generated reactive oxygen species . In
the presence of hypercholesterolemia, caveolin, an essential protein component of caveolae, binds to eNOS,
[21]
leading to an inactivity of eNOS .
LDL
LDL interactions with the endothelium have been closely associated with accelerated atherosclerosis [20,21] .
LDLs and ox-LDLs activate EC NADPH oxidases, generating reactive oxygen species [21,33] . LDLs and ox-LDLs
also cause increases in the binding of eNOS to CD36, and consequently the attenuation of eNOS activity
[34]
and the displacement of the protein from EC caveolae are induced . Additionally, the interactions between
eNOSs and NADPH oxidases determine the production of nitric oxide and reactive oxygen species, because
[35]
nitric oxide produced adjacent to NADPH oxidases is scavenged by reactive oxygen species . Furthermore,
[21]
native LDLs increase the expressions of ICAM-1, VCAM-1, and p-selectin .
Triglyceride and TG-rich lipoprotein
Triglyceride (TG) is a major component of TG-rich lipoprotein (TGRL) including chylomicrons (CMs), very
LDLs (VLDLs) and their remnants. TG and TGRL contribute directly to the development and progression of

atherosclerotic plaque.While CMs and larger VLDLs cannot penetrate the arterial walls, their smaller TGRL
remnants not only penetrate the arterial intima, but also promote the binding and retention to connective
[36]
tissue matrix . This transcytosis involvement in the transport system is restricted to a lipoprotein with a
diameter of ≤ 60-70 nm. TGRL remnants carry about 40 times more Cho per particle compared with LDLs,
[36]
due to their larger size . Accumulation of CMs and VLDLs with abundant Apo E have been shown in
an atherosclerotic plaque. Macrophages directly take up such particles, and resultantly have massive Cho
loading, leading to the formation of foam cells.

TG and TGRL also accelerate the atherogenesis through an indirect mechanism, particularly that involving
binding and lipolysis at the arterial walls [37-40] . TGRL increases the production of reactive oxygen species,
[37]
secretion of tumor necrosis factor-α, and expressions of CAMs . A high level of TGs leads to TGRLs
enriched with Apo C-III, and influences signaling pathways, which lead to activation of nuclear factor
(NF)-κB and upregulation of inflammatory mediators, causing the development of fatty streaks and the
[38]
advancement of atherosclerosis . CM remnants migrate to the subendothelial space, activate leukocytes,
and accelerate the formation of foam cells: CM also activates monocytes, and enhances migration of
[39]
monocytes and postprandial neutrophils . TG in the presence of an elevated concentration of VLDL
generates small dense LDL, which is particularly atherogenic, since these particles are retained preferentially
by the arterial walls. Furthermore, elevated TG is linked with procoagulant states by increasing factor VII,
and activating factor VII phospholipid complexes, factor X, factor XII, tissue plasminogen activator inhibitor,
and thrombin generation [21,40] .