Diesel exhaust particles induce a two-stage program of myocardial oxidative stress involving NADPH oxidases and...

Air pollution-associated cardiovascular morbidity is strongly linked to oxidative stress. We previously showed that diesel exhaust particles (DEPs) exposure increases arrhythmia inducibility in rats, effect associated with myocardial reactive oxygen species (ROS) generation and inflammation. However, the upstream mechanisms driving ROS production remain unclear.

To investigate the sources and temporal regulation of myocardial ROS after DEP exposure in rats and assess the effects of cerium oxide nanoparticles (CeO₂NPs).

Male and female Sprague-Dawley rats received intratracheal instillations of saline containing or not DEPs for one or three weeks, with or without CeO₂NP. Expression and activity of ROS-producing and detoxifying enzymes were analyzed by RT-PCR and chemiluminescence. Oxygen consumption and ROS production were measured in isolated cardiac mitochondria under baseline conditions and after incubation with malate and glutamate.

DEP exposure induced a transient early upregulation of NADPH oxidase (NOX) isoforms, with increased mitochondrial NOX activity after one week. This effect associated with sustained downregulation of the mitochondrial antioxidant enzyme thioredoxin reductase 2. After three weeks, DEP exposure reduced citrate synthase activity in subsarcolemmal and interfibrillar mitochondria and mitochondrial DNA copy number, indicating reduced mitochondrial content, and increased mitochondrial ROS production, especially during complex I-dependent respiration. CeO₂NP treatment ameliorated NOX4 upregulation, preserved mitochondrial content, and attenuated mitochondrial ROS generation.

These findings support a two-hit model of DEP-induced myocardial oxidative stress, characterized by an early increase in NOX expression and activity followed by sustained mitochondrial ROS production. Redox-active biocompatible nanomaterials may mitigate air pollution-induced cardiac injury.