Exposure to the Dioxin-like Pollutant PCB 126 Afflicts Coronary Endothelial Cells via Increasing 4-Hydroxy-2 Nonenal: A Role for Aldehyde Dehydrogenase 2

Toxics

Manisha Agarwal¹  Suresh Selvaraj Palaniyandi²  Guodong Pan²  Bipradas Roy²  Katherine Roth³  Rahul Sharma³  Michael C. Petriello³  Zhao Yang³ 

[1] Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI 48202, USA;Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI 48202, USA;Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USA;

关键词: angiogenesis;    3, 3′, 4, 4′, 5-pentachlorobiphenyl (PCB 126);    environmental pollutants;    coronary endothelial cells;    aldehyde dehydrogenase 2;    4-hydroxy-2-nonenal;   

DOI  :  10.3390/toxics10060328

来源: DOAJ

【 摘 要 】

Exposure to environmental pollutants, including dioxin-like polychlorinated biphenyls (PCBs), play an important role in vascular inflammation and cardiometabolic diseases (CMDs) by inducing oxidative stress. Earlier, we demonstrated that oxidative stress-mediated lipid peroxidation derived 4-hydroxy-2-nonenal (4HNE) contributes to CMDs by decreasing the angiogenesis of coronary endothelial cells (CECs). By detoxifying 4HNE, aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme, enhances CEC angiogenesis. Therefore, we hypothesize that ALDH2 activation attenuates a PCB 126-mediated 4HNE-induced decrease in CEC angiogenesis. To test our hypothesis, we treated cultured mouse CECs with 4.4 µM PCB 126 and performed spheroid and aortic ring sprouting assays, the ALDH2 activity assay, and Western blotting for the 4HNE adduct levels and real-time qPCR to determine the expression levels of Cyp1b1 and oxidative stress-related genes. PCB 126 increased the gene expression and 4HNE adduct levels, whereas it decreased the ALDH2 activity and angiogenesis significantly in MCECs. However, pretreatment with 2.5 µM disulfiram (DSF), an ALDH2 inhibitor, or 10 µM Alda 1, an ALDH2 activator, before the PCB 126 challenge exacerbated and rescued the PCB 126-mediated decrease in coronary angiogenesis by modulating the 4HNE adduct levels respectively. Finally, we conclude that ALDH2 can be a therapeutic target to alleviate environmental pollutant-induced CMDs.

【 授权许可】

Unknown