A new mechanism involved in cardiovascular senescence induced by environmentally relevant dose of 16 priority-controlled PAHs

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are closely related to the occurrence of cardiovascular diseases, nevertheless the toxicological mechanism remains ambiguous. To verify whether PAHs exposure leads to cardiovascular senescence, 8-week-old male sprague–dawley rats and primary human umbilical vein endothelial cells were exposed to different concentrations of 16 priority-controlled PAHs for 90 d and 48 h respectively. In in vitro study, PAHs exposure promoted aryl hydrocarbon receptor (AhR) activation, and then directly or indirectly inhibited SIRT6 expression leading to telomere dysfunction, which further caused DNA damage and subsequently promoted endothelial cells senescence. But the treatment of CH-223191 (an AhR inhibitor) rescued the aging phenotypes induced by PAHs, suggesting that AhR plays an important role in PAHs-induced endothelial cells senescence. In in vivo study, PAHs exposure raised AhR expression, affected SIRT6-related aging signaling pathway, and induced myocardial and vascular remodeling in rats. Molecular dynamics simulations demonstrated that, in addition to benzo[a]pyrene-7,8-diol-9,10-epoxide (the mediate metabolite of benzo[a]pyrene), typical parent PAHs (phenanthrene, benzo[a]pyrene) can directly bind to known DNA strand binding sites of SIRT6 through hydrophobic force, which was further validated by electrophoretic mobility shift assay. All above indicates for the first time that in addition to classical AhR dependent pathway, parent PAHs may affect DNA damage response and telomere maintenance function of SIRT6, which is a new mechanism of PAHs induced cardiovascular senescence.