资源环境科技发展态势分析平台

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 ($Apo{E}^{-/-}$) 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 $Apo{E}^{-/-}$ mice and apolipoprotein E/caveolin 1 double-knockout ($Apo{E}^{-/-}/CAV{1}^{-/-}$) 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 $\text{factor-}\mathrm{\beta }2$ ($TGF\text{-}\mathrm{\beta }2$) as a possible target gene of MIR-7-5p; HDAC7-AS1 sponged MIR-7-5p and inhibited the binding of $TGF\text{-}\mathrm{\beta }2$ to MIR-7-5p. The effect of PCB29-pQ–induced endothelial injury, vascular inflammation, development of plaques, and atherogenesis in $Apo{E}^{-/-}$ mice was greater with MIR-7-5p–mediated $TGF\text{-}\mathrm{\beta }2$ inhibition, whereas HDAC7-AS1–overexpressing $Apo{E}^{-/-}$ mice and $Apo{E}^{-/-}/CAV{1}^{-/-}$ 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 $Apo{E}^{-/-}$ and $Apo{E}^{-/-}/CAV{1}^{-/-}$ mice. https://doi.org/10.1289/EHP9833