VITAMIN D DEFICIENCY AND AIR POLLUTION: EFFECTS IMPACTING THE CARDIOVASCULAR SYSTEM

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  • March 22, 2019
Creator
  • Stratford, Kimberly
    • Affiliation: School of Medicine, Curriculum in Toxicology
Abstract
  • Human studies have shown that air pollution is associated with cardiovascular morbidity, yet the role of nutrition in modifying this susceptibility is unclear. Vitamin D deficiency (VDD) is a public health concern and the adverse consequences of its interaction with other stressors is understudied. VDD is linked to low levels of klotho, an anti-aging protein with a critical role in sinoatrial function. Transient receptor potential (TRP) channels are regulated by klotho and mediate cardiac effects to air pollution. TRPC6 is a cation channel that is physiologically inactive under normal conditions but upregulated with cardiovascular disease. I hypothesized that VDD changes cardiovascular function through mechanisms involving klotho and TRPC6 that mediate the responses to air pollution. First, I determined the effect of early-life VDD on cardiovascular responses to photochemical smog in mice. Three-week-old mice were placed on either a VDD or normal diet for 16-19 weeks and surgically implanted with biopotential radiotelemeters to continuously measure electrocardiogram, heart rate (HR) and whole-body plethysmography (WBP) for arrhythmias, heart rate variability (HRV) and ventilatory function. This study shows that VDD mice had decreased HR/tidal volume and increased HRV compared to controls and smog modulated the response. Second, I determined the role of klotho in VDD-induced adverse cardiac response to acrolein exposure. Mice were treated with recombinant klotho to determine if the potentiated effects are blocked. This study demonstrates that compared to controls, HR/HRV was decreased in VDD mice. When compared to air exposure, acrolein increased HR/HRV and klotho blocked acrolein-induced effects in both diets. Lastly, I investigated the role of TRPC6 in VDD-induced cardiovascular mechanical responses. Dobutamine stress test was used to increase heart rate and reveal latent cardiac effects due to VDD and the involvement of TRPC6 in VDD mice was determined using an antagonist. Compared to controls, VDD mice have higher blood pressure and blunted HR response to dobutamine which was restored by TRPC6 antagonist. Future studies are needed to evaluate klotho and TRPC6 as potential therapeutic interventions. This project is the first to characterize the role of VDD as a nutritional modifiable factor in relation to cardiovascular toxicological responses to stressors.
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Advisor
  • Hazari, Mehdi
  • Voruganti, V. Saroja
  • Diaz-Sanchez, David
  • Styblo, Mirek
  • Qian, Li
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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