Polycyclic aromatic hydrocarbons induce an inflammatory atherosclerotic plaque phenotype irrespective of their DNA binding properties
Schooten, van, Frederik J.
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Faculty of Medicine and Health Sciences
The FASEB journal / Federation of American Societies for Experimental Biology. - Bethesda, Md
, p. 1290-+
University of Antwerp
Although it has been demonstrated that carcinogenic environmental polycyclic aromatic hydrocarbons (PAHs) cause progression of atherosclerosis, the underlying mechanism remains unclear. In the present study, we aimed to investigate whether DNA binding events are critically involved in the progression of PAH-mediated atherogenesis. Apolipoprotein E knockout mice were orally (24 wk, once/wk) exposed to 5 mg/kg benzo[a] pyrene ( B[a] P), or its nonmutagenic, noncarcinogenic structural isoform benzo[e] pyrene ( B[e] P). P-32-postlabeling of lung tissue confirmed the presence of promutagenic PAH-DNA adducts in B[a] P-exposed animals, whereas in B[e] P-exposed and vehicle control animals, these adducts were undetectable. Morphometrical analysis showed that both B[a] P and B[e] P caused an increase in plaque size, whereas location or number of plaques was unaffected. Immunohistochemistry revealed no differences in oxidative DNA damage (8-OHdG) or apoptosis in the plaques. Also plasma lipoprotein levels remained unchanged after PAH-exposure. However, T lymphocytes were increased >= 2-fold in the plaques of B[a]P- and B[e] P- exposed animals. Additionally, B[a] P and to a lesser extent B[e] P exposure resulted in increased TGF beta protein levels in the plaques, that was mainly localized in the plaque macrophages. In vitro studies using the murine macrophage like RAW264.7 cells showed that inhibition of TGF beta resulted in decreased tumor necrosis factor (TNF) alpha release, suggesting that enhanced TGF beta expression in the plaque macrophages contributes to the proinflammatory effects in the vessel wall. In general, this inflammatory reaction in the plaques appeared to be a local response since peripheral blood cell composition ( T cells, B cells, granulocytes, and macrophages) was not changed upon PAH exposure. In conclusion, we showed that both B[a] P and B[e] P cause progression of atherosclerosis, irrespective of their DNA binding properties. Moreover, our data revealed a possible novel mechanism of PAH-mediated atherogenesis, which likely involves a TGF-mediated local inflammatory reaction in the vessel wall.