Evaluation of Early Biomarkers of Atherosclerosis Associated with Polychlorinated Biphenyl Exposure: An <i>in Vitro</i> and <i>in Vivo</i> Study
Bingwei Yang, Zhishuai Ye, Yawen Wang, Hongzhou Guo, Hans-Joachim Lehmler, Rongchong Huang, Erqun Song, Yang Song
Abstract
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 (ApoE−/−) 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 ApoE−/− mice and apolipoprotein E/caveolin 1 double-knockout (ApoE−/−/CAV1−/−) 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-β2 (TGF-β2) as a possible target gene of MIR-7-5p; HDAC7-AS1 sponged MIR-7-5p and inhibited the binding of TGF-β2 to MIR-7-5p. The effect of PCB29-pQ–induced endothelial injury, vascular inflammation, development of plaques, and atherogenesis in ApoE−/− mice was greater with MIR-7-5p–mediated TGF-β2 inhibition, whereas HDAC7-AS1–overexpressing ApoE−/− mice and ApoE−/−/CAV1−/− 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 ApoE−/− and ApoE−/−/CAV1−/− mice. https://doi.org/10.1289/EHP9833