摘要：Background:
Miscellaneous cardiovascular risk factors have been defined, but the contribution of environmental pollutants exposure on cardiovascular disease (CVD) remains underappreciated.
Objective:
We investigated the potential impact of typical environmental pollutant exposure on atherogenesis and its underlying mechanisms.
Methods:
We used human umbilical vein endothelial cells (HUVECs) and apolipoprotein E knockout (
A
p
o
E
−
/
−
) mice to investigate how 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone (PCB29-pQ, a toxic polychlorinated biphenyl metabolite) affects atherogenesis and identified early biomarkers of CVD associated with PCB29-pQ exposures. Then, we used long noncoding RNAs (lncRNAs)
HDAC7-AS1–overexpressing
A
p
o
E
−
/
−
mice and apolipoprotein E/caveolin 1 double-knockout (
A
p
o
E
−
/
−
/
C
A
V
1
−
/
−
) mice to address the role of these early biomarkers in PCB29-pQ–induced atherogenesis. Plasma samples from patients with coronary heart disease (CHD) were also used to confirm our findings.
Results:
Our data indicate that lncRNA
HDAC7-AS1 bound to
MIR-7-5p via argonaute 2 in PCB29-pQ–challenged HUVECs. Our mRNA sequencing assay identified transforming growth
factor-
β
2
(
T
G
F
-
β
2
) as a possible target gene of
MIR-7-5p;
HDAC7-AS1 sponged
MIR-7-5p and inhibited the binding of
T
G
F
-
β
2
to
MIR-7-5p. The effect of PCB29-pQ–induced endothelial injury, vascular inflammation, development of plaques, and atherogenesis in
A
p
o
E
−
/
−
mice was greater with
MIR-7-5p–mediated
T
G
F
-
β
2
inhibition, whereas
HDAC7-AS1–overexpressing
A
p
o
E
−
/
−
mice and
A
p
o
E
−
/
−
/
C
A
V
1
−
/
−
mice showed the opposite effect. Consistently, plasma levels of
HDAC7-AS1 and
MIR-7-5p were found to be significantly associated individuals diagnosed with CHD.
Discussions:
These findings demonstrated that a mechanism-based, integrated-omics approach enabled the identification of potentially clinically relevant diagnostic indicators and therapeutic targets of CHD mediated by environmental contaminants using
in vitro and
in vivo models of HUVECs and
A
p
o
E
−
/
−
and
A
p
o
E
−
/
−
/
C
A
V
1
−
/
−
mice.
https://doi.org/10.1289/EHP9833
