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Transient receptor potential cation channel A1 (TRPA1) mediates decrements in cardiac mechanical function and dysrhythmia caused by a single air pollution exposure in mice
Citation:
Kurhanewicz, N., R. McIntosh-Kastrinsky, A. Ledbetter, L. Walsh, A. Farraj, AND M. Hazari. Transient receptor potential cation channel A1 (TRPA1) mediates decrements in cardiac mechanical function and dysrhythmia caused by a single air pollution exposure in mice. Presented at Society of Toxicology, Phoenix, AZ, March 23 - 27, 2014.
Impact/Purpose:
This work examines the mechanisms of air pollution-induced cardiovascular effects; specifically, the role of TRPA1, which is an irritant "sensor" in the nose and lungs.These studies seek to answer important agency questions onthe impact of air pollution on human health.
Description:
This work, which will be presented at SOT 2014, demonstrates that a single exposure to either ozone or acrolein causes decrements in cardiac function and altered electrical activity (i.e. arrhythmia). The results suggest that this effect is mediated by the airway sensor TRPA1. Time-series studies indicate that the risk of cardiac events and arrhythmia increase significantly in the hours to days directly following exposure to air pollution. Previous studies have demonstrated that pharmacological inhibition of transient receptor potential cation A1 (TRPA1) attenuates diesel exhaust-induced cardiac arrhythmia. In this study, we sought to further confirm the role of TRPA1 in acute cardiovascular dysfunction due to air pollution exposure by utilizing a TRPA1 knockout mouse model. We hypothesized that acrolein and ozone (O3), both potent TRPA1 agonists, would cause decrements in cardiac function and electrical disturbances through TRPA1 mediated mechanisms. Conscious, unrestrained C57BL/6 (wt) and TRPA1 knockout (ko) mice surgically implanted with radiotelemeters were exposed by whole body inhalation to 3ppm acrolein for 3 hours, or 0.3ppm O3 for 4 hours; separate groups were exposed to filtered air (FA). Heart rate (HR) and electrocardiogram (ECG) were recorded continuously before, during and after exposure and later analyzed for arrhythmia. 24 hours post-exposure, cardiac function was assessed using a Langendorff cardiac perfusion preparation. Coronary flow, left ventricular developed pressure (LVDP) and contractility were measured before and after cardiac ischemia/reperfusion (I/R) injury. Acrolein exposed wt mice demonstrated a significant decrease in HR during exposure as well as an increased incidence of non-conducted p-wave arrhythmia, compared with FA controls. Acrolein also produced a significant increase in ventricular relaxation, whereas exposure to O3 produced a significant decrease in contractility and relaxation in wt mice. No effects were observed in acrolein or O3 exposed ko mice. These data indicate that TRPA1 mediates, at least in part, the development of acute cardiac function decrements and dysrhythmia following exposure to either of these two relatively ubiquitous pollutants. Although both acrolein and O3 are TRPA1 agonists, they appear to cause divergent cardiac responses, which suggest the underlying mechanisms are more complex than mere sensory activation. (This abstract does not reflect EPA policy)