Abstract P349: Ambient Air Pollution Compromises Nitric Oxide Bioavailability, Leading to Accelerated Endothelial Cell Senescence

Abstract

Particulate matter (PM) pollution is a burden to public health. Although PM causes a health risk to the lung, the overall evidence indicates that the majority of the PM effects are upon the cardiovascular system. Several studies demonstrated that ultrafine particles can directly enter the circulation and thus may interact with endothelial cells. However, intracellular mechanisms affected by non-cytotoxic, in vivo relevant concentrations of particles have not been investigated in endothelial cells in vitro and in vivo. Therefore, this study aims for the first time to analyze the effects of ultrafine and fine particles of different materials in non-toxic concentrations on human endothelial cells (EC) and in animals. We incubated EC with ultrafine and fine Carbon Black (ufCB and fCB) particles as well as Titaniumdioxide (ufTiO2 and fTiO2) and determined the non-toxic concentrations. MTT measurements revealed that 0.1 and 1 µg/cm2 did not reduce endothelial cell viability. To test whether these concentrations influence endothelial cell function, we measured nitric oxide (NO) bioavailability, which is important for vessel function. Only ultrafine particles reduced the S-NO content of EC, whereas fine particles had no effect at the same concentrations. Interestingly, the effects observed with ufCB and ufTiO2 were more pronounced than with the known reducer of NO bioavailability, H2O2. We previously demonstrated that NO increases activation of Telomerase Reverse Transcriptase (TERT), an enzyme essential for telomere maintenance. TERT activation is required to protect EC from apoptosis and the onset of senescence and TERT is inactivated by the Src kinase under conditions of oxidative stress. Therefore, we investigated the effects of ufCB and ufTiO2 on TERT and Src activation. ufCB and ufTiO2 significantly reduced TERT and increased Src kinase activation. To investigate whether ufCB show also effects in vivo, we instilled ufCB into rats and determined eNOS and TERT expression in the aorta. ufCB reduced eNOS and TERT expression in the abdominal aorta of animals treated with ufCB. Thus, ultrafine nanoparticles, which we inhale every day, seem to reduce endothelial function and thus should be considered a risk factor for cardiovascular disease.