Impairment of sirtuin 1-mediated DNA repair is involved in bisphenol A-induced aggravation of macrophage inflammation and atherosclerosis

Abstract

Bisphenol A (BPA), an environmental pollutant, has received considerable attention worldwide for its hazardous effects of promoting atherosclerosis and increasing the risk of cardiovascular diseases (CVDs). However, the mechanisms involved are unclear. We aimed to investigate the mechanisms underlying BPA-aggravated atherosclerosis and potential preventive treatments. Four-week-old male Ldlr^-/- C57BL/6 mice were administered 250 μg/L BPA via drinking water for 30 weeks with or without a Western diet and/or resveratrol (RESV) for 12 weeks. Chronic BPA exposure significantly aggravated atherosclerosis, enhanced the production of inflammatory cytokines but not lipid levels, promoted macrophage infiltration into plaque areas. Moreover, peritoneal macrophages isolated from BPA-exposed mice exhibited a more pro-inflammatory phenotype in response to cholesterol crystal treatment than those from control mice. The comet assay revealed that the DNA repair capacity of BPA-exposed macrophages was impaired, and western blotting showed that sirtuin 1 and Nijmegen breakage syndrome 1 (NBS1) expression was reduced. However, restoring sirtuin 1 by RESV administration significantly blocked the BPA-induced decrease in NBS1 and subsequently attenuated the BPA-induced impairment of DNA repair and apoptosis, as indicated by phosphorylated H2AX expression and staining and PARP expression. Moreover, RESV administration significantly ameliorated BPA-aggravated NOD-like receptor pyrin domain 3 and caspase 1 activation and interleukin-1β production, which were abolished by NBS1 knockdown. Furthermore, RESV administration prevented BPA-induced aggravation of atherosclerosis. Our findings indicate that impairment of sirtuin 1-mediated DNA repair is involved in BPA-induced aggravation of macrophage inflammation and atherosclerosis and that RESV might be a promising preventive and therapeutic agent for BPA-related CVDs.

Keywords: Atherosclerosis; Bisphenol A; DNA repair; Macrophage inflammation; Sirtuins.