Long-term nicotine intake is associated with an increased risk of myocardial damage and dysfunction. However, it remains unclear whether targeting mitochondrial reactive oxygen species (ROS) prevents nicotine-induced cardiac remodeling and dysfunction. This study investigated the effects of mitoTEMPO (a mitochondria-targeted antioxidant), and resveratrol (a sirtuin activator) , on nicotine-induced cardiac remodeling and dysfunction. Sprague-Dawley rats were administered 0.6 mg/kg nicotine daily with 0.7 mg/kg mitoTEMPO, 8 mg/kg resveratrol, or vehicle alone for 28 days. At the end of the study, rat hearts were collected to analyze the cardiac structure, mitochondrial ROS level, oxidative stress, and inflammation markers. A subset of rat hearts was perfused ex vivo to determine the cardiac function and myocardial susceptibility to ischemia-reperfusion injury. Nicotine administration significantly augmented mitochondrial ROS level, cardiomyocyte hypertrophy, fibrosis, and inflammation in rat hearts. Nicotine administration also induced left ventricular dysfunction, which was worsened by ischemia-reperfusion in isolated rat hearts. MitoTEMPO and resveratrol both significantly attenuated the adverse cardiac remodeling induced by nicotine, as well as the aggravation of postischemic ventricular dysfunction. Findings from this study show that targeting mitochondrial ROS with mitoTEMPO or resveratrol partially attenuates nicotine-induced cardiac remodeling and dysfunction.
This study investigated the impact of prolonged nicotine administration on myocardial susceptibility to ischaemia-reperfusion (I/R) injury in a rat model and determined whether nicotine affects mitochondrial reactive oxygen species (ROS) production and permeability transition in rat hearts. Sprague-Dawley rats were administered 0.6 or 1.2 mg/kg nicotine for 28 days, and their hearts were isolated at end-point for assessment of myocardial susceptibility to I/R injury ex vivo. Rat heart mitochondria were also isolated from a subset of rats for analysis of mitochondrial ROS production and permeability transition. Compared to the vehicle controls, rat hearts isolated from nicotine-administered rats exhibited poorer left ventricular function that worsened over the course of I/R. Coronary flow rate was also severely impaired in the nicotine groups at baseline and this worsened after I/R. Nicotine administration significantly increased mitochondrial ROS production and permeability transition relative to the vehicle controls. Interestingly, pre-incubation of isolated mitochondria with ROS scavengers (superoxide dismutase and mitoTEMPO) significantly abolished nicotine-induced increase in mitochondria permeability transition in isolated rat heart mitochondria. Overall, our data showed that prolonged nicotine administration enhances myocardial susceptibility to I/R injury in rats and this is associated with mitochondrial ROS-driven increase in mitochondrial permeability transition.