Biomedical Engineering Reference
In-Depth Information
Homocysteine interferes with proper disulfide bond formation
and its oxidation to homocystine is a source for ROS, which dam-
age proteins by carbonylation of the peptide backbone, and also
reversibly or irreversibly activate ryanodine Ca
2+
release channels
in the ER membrane. Through a combination of these mecha-
nisms homocysteine prevents transport of thrombomodulin (
95
)
and von Willebrand factor to the cell surface (
96
), and induces
UPR markers such as BiP, GRP94, CHOP, and HERP (
97
),
damaging the endothelial cell layer and contributing to initiation
of atherosclerosis (Fig.
4
). Homocysteine also activates lipogenic
signaling via the SREBPs leading to cholesterol accumulation
(
98
), which contributes to the development of ER stress in hyper-
homocysteinemia and fatty liver disease.
chop
−/−
mice were pro-
tected from alcohol-induced hepatic apoptosis, but not ER stress,
fatty liver, or hyperhomocysteinemia (
99
), suggesting that apop-
totic cell death in response to alcohol abuse or hyperhomo-
cysteinemia is triggered by ER stress signaling pathways.
Atherosclerosis is a major cause for myocardial infarction, stroke,
and heart disease. Damage of the vascular endothelial cell layer
allows formation of lipid-, especially cholesterol-rich deposits of
low density lipoprotein (LDL) in the subendothelial intima
(Fig.
4
) (
100
). LDL oxidation induces endothelial cells to pro-
duce inflammatory cytokines such as monocyte chemoattractant
protein-1 (MCP-1) leading to invasion of the intima by mono-
cytes, which then differentiate into macrophages. These mac-
rophages endocytose highly oxidized LDL, which is produced by
ROS released by endothelial cells and macrophages. Cholesterol
esterification transforms macrophages into foam cells. Macrophages
secrete apolipoprotein E (apoE), which promotes cholesterol
efflux to high density lipoproteins (HDL) (
100
). Release of lip-
ids, mostly cholesterol and cholesterol esters by dying foam cells
contributes to formation of fibrous plaques, which may initiate
thrombosis (
100
). ER stress plays important roles in two stages of
atherosclerosis (Fig.
4
). ER stress is involved in initial damage of
the vascular endothelial layer in hyperhomocysteinemia (
101-
104
) by inducing endothelial cell apoptosis via the IRE1a-JNK
pathway (
103
). Atherosclerotic lesion-resident macrophages dis-
play markers of UPR activation (
104, 105
), including PERK
phosphorylation, and expression of CHOP, ATF4, and spliced
XBP-1 (
106
).
perk
−/−
macrophages are sensitized to, whereas
chop
−/−
macrophages are protected from cholesterol-induced
apoptosis (
106
). Cholesterol induces ER stress by decreasing the
fluidity of the ER membrane, resulting in inhibition of SERCA
Ca
2+
pumps and Ca
2+
depletion of the ER (
106, 107
). Thus, ER
stress may be responsible for foam cell death and formation of
the necrotic core of fibrous plaques. Cholesterol activation of the
UPR in macrophages also contributes to production of
3.6. Atherosclerosis
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