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Polycyclic aromatic hydrocarbons induce an inflammatory atherosclerotic plaque phenotype irrespective of their DNA binding properties
Author(s) -
Curfs Daniëlle M. J.,
Knaapen Ad M.,
Pachen Daniëlle M. F. A.,
Gjbels Marion J. J.,
Lutgens Esther,
Smook Marjan L. F.,
Kockx Mark M.,
Daemen Mat J. A. P.,
Schooten Frederik J.
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-2269fje
Subject(s) - carcinogen , chemistry , proinflammatory cytokine , dna damage , benzo(a)pyrene , pyrene , tumor necrosis factor alpha , microbiology and biotechnology , macrophage , apoptosis , inflammation , apolipoprotein b , knockout mouse , dna , in vitro , immunology , biology , biochemistry , cholesterol , receptor , organic chemistry
ABSTRACT 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). 32 P‐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 TGFβ 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 TGFβ resulted in decreased tumor necrosis factor (TNF) α release, suggesting that enhanced TGFβ 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 TGFβ‐mediated local inflammatory reaction in the vessel wall.