Abstract 4141905: ROS-Detoxifying Cerium Oxide Nanoparticles Attenuate the Pro-Arrhythmic Effect of Diesel Exhaust Particles in Isolated Rat Hearts

Introduction: Epidemiological evidence suggests a link between acute air pollution exposure and ventricular arrhythmias, with increased reactive oxygen species (ROS) production as a key mechanism. However, a cause-effect relationship remains unclear, studies on chronic effects are lacking, and the impact of strategies limiting ROS production has not been studied in detail. Aims: To analyze the effects of chronic intratracheal instillation of diesel exhaust particles (DEPs) on ventricular arrhythmogenesis, investigate the underlying mechanisms, and assess the impact of cerium oxide nanoparticles (CeO 2 NP) as a ROS-detoxifying strategy. Methods: Male and female Sprague-Dawley rats were intratracheally instilled with saline without or with DEPs (7.5 g/Kg, 0.375 mL/Kg, 3 times/week, for 1-3 weeks). Rats were then sacrificed and hearts perfused through the aorta in a Langendorff system. Incidence of premature ventricular beats (PVBs) and non-sustained and sustained (>30s) ventricular tachyarrhythmias (VT) were assessed by programmed electrical stimulation. Cardiac hypertrophy, collagen content, inflammation and oxidative stress were analyzed by conventional histology, Western Blot, RT-PCR, and the oxidized/reduced glutathione (GSH/GSSG) ratio. The potential protective effect of ROS-detoxifying CeO 2 NP (0.5 mg/Kg/week, i.p.) was also analyzed. Results: DEP exposure increased the incidence and duration of inducible sustained VTs. This pro-arrhythmic effect associated with a moderate rise in interstitial collagen deposition (from 3.11±0.12 in controls to 4.80±0.21 % in DEP-exposed rats, Student’s t test, p<0.001) and prolonged QRS complex and QTc in the ECG. Collagen expression was induced within one weeks of DEP exposure, as shown by RT-PCR. Additionally, the GSH/GSSG ratio decreased after 3 weeks of DEP exposure, while mRNA levels of the ROS-producing NOX1, NOX2 and NOX4 isoforms rose early after DEP exposure, and expression of the antioxidant thioredoxin reductase was reduced. CeO 2 NP attenuated the pro-arrhythmic effects of DEP exposure (sustained VT duration: 0.00±0.00, 51.09±18.99 and 20.00±20.00 ms in hearts from control, DEP-treated and CeO 2 -treated animals, Krustal-Wallis test, p<0.05 between controls and DEP-treated). Conclusion: DEP exposure increases the incidence and duration of sustained VTs in rats, effects associated with increased collagen deposition and oxidative stress. ROS-detoxifying CeO 2 NP attenuate the pro-arrhythmic effects of DEP exposure.