Deficiency of TDAG51 Protects Against Atherosclerosis by Modulating Apoptosis, Cholesterol Efflux, and Peroxiredoxin‐1 Expression
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abstract
Background
Apoptosis caused by endoplasmic reticulum (
ER
) stress contributes to atherothrombosis, the underlying cause of cardiovascular disease (
CVD
).
T
‐cell death‐associated gene 51 (
TDAG51
), a member of the pleckstrin homology‐like domain gene family, is induced by
ER
stress, causes apoptosis when overexpressed, and is present in lesion‐resident macrophages and endothelial cells.
Methods and Results
To study the role of
TDAG51
in atherosclerosis, male mice deficient in
TDAG51
and
apolipoprotein E
(
TDAG51−/−
/
ApoE−/−
) were generated and showed reduced atherosclerotic lesion growth (56±5% reduction at 40 weeks, relative to
ApoE−/−
controls,
P
<0.005) and necrosis (41±4% versus 63±8% lesion area in
TDAG51−/−/ApoE−/−
and
ApoE−/−
, respectively;
P
<0.05) without changes in plasma levels of lipids, glucose, and inflammatory cytokines.
TDAG51
deficiency caused several phenotypic changes in macrophages and endothelial cells that increase cytoprotection against oxidative and
ER
stress, enhance
PPAR
γ‐dependent reverse cholesterol transport, and upregulate peroxiredoxin‐1 (Prdx‐1), an antioxidant enzyme with antiatherogenic properties (1.8±0.1‐fold increase in Prdx‐1 protein expression, relative to control macrophages;
P
<0.005). Two independent case–control studies found that a genetic variant in the human
TDAG51
gene region (rs2367446) is associated with
CVD
(
OR
, 1.15; 95%
CI
, 1.07 to 1.24;
P
=0.0003).
Conclusions
These findings provide evidence that
TDAG51
affects specific cellular pathways known to reduce atherogenesis, suggesting that modulation of
TDAG51
expression or its activity may have therapeutic benefit for the treatment of
CVD
.
