The Role of TRPA1 and Autonomic Imbalance in the Cardiac Response to Air Pollution Public Deposited

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  • March 20, 2019
Creator
  • Kurhanewicz, Nicole
    • Affiliation: School of Medicine, Curriculum in Toxicology
Abstract
  • Exposure to air pollution has been shown to contribute to cardiovascular morbidity and mortality; this is especially true for certain susceptible subpopulations. One mechanism linking air pollution and cardiovascular dysfunction involves perturbation of autonomic nervous system balance initiated by air pollution activation of airway sensory receptors. One such “sensor” is transient receptor potential A1 cation channel (TRPA1), which is expressed on airway afferent nerves and is known to be activated by certain ubiquitous air pollutants. Although this mechanism has classically been known to mediate certain reflexive respiratory responses, research suggests that a subset of cardiovascular responses are similarly produced. Thus my global hypothesis for this dissertation project is that autonomic imbalance during an acute exposure to air pollution, as indicated by heart rate variability (HRV), is mediated by TRPA1 and contributes to cardiac dysfunction. To test this, we first characterized the cardiovascular response of mice to acute particulate matter and ozone exposure. We then examined the cardiovascular impacts of inhaled acrolein, which is a TRPA1 agonist, in both wild-type and TRPA1 knockout mice. Lastly we determined if inhibition of either or both arms of the autonomic nervous system affected the acrolein-induced changes HRV. Co-exposure to fine or ultrafine concentrated ambient particles and ozone produced ECG changes indicative of increased heterogeneity of repolarization, non-conducted p-wave arrhythmias, and decrements in cardiac mechanical function one day after exposure. Exposure to acrolein caused increases in HRV and bradyarrhythmia during exposure, as well as changes in cardiac mechanical function one day after exposure. No exposure effects were observed in the TRPA1 knockout mouse. Pharmacological inhibition of either or both arms of the autonomic nervous system demonstrated that acrolein exposure caused a biphasic response in which early sympathetic activation was followed by prolonged vagal dominance. These data suggest that air pollution causes autonomic imbalance and cardiac dysfunction through TRPA1. This research fills important gaps in our understanding of mechanisms underlying air pollution-induced cardiovascular dysfunction and will aid in risk assessment.
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  • In Copyright
Advisor
  • Jensen, Brian
  • Zylka, Mark J.
  • Costa, Daniel
  • Hazari, Mehdi
  • Peden, David
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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