Date on Master's Thesis/Doctoral Dissertation

5-2020

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Conklin, Daniel

Committee Co-Chair (if applicable)

Bhatnagar, Aruni

Committee Member

Bhatnagar, Aruni

Committee Member

Hoyle, Gary

Committee Member

Keith, Rachel

Committee Member

Wise Sr., John

Author's Keywords

Cardiovascular disease; tobacco products; aldehydes; electronic cigarettes; circulating angiogenic cells

Abstract

Cardiovascular disease (CVD) is the leading cause of death worldwide. Tobacco smoke is the most significant modifiable risk factor in CVD development and contains numerous toxic compounds, including aldehydes, which have been linked to CVD. Formaldehyde, acetaldehyde, acrolein, and crotonaldehyde have been identified as significant contributors to cigarette-induced health effects, but the mechanism of these effects is not well understood. These aldehydes are also found in aerosols produced by e-cigarettes (e-cigs). The goal of this dissertation was to explore the systemic, hematological, and endothelium-related effects of exposure to tobacco products and constituent aldehydes and to identify potential mechanisms of injury. In the Louisville Healthy Heart Study, hematological measures and circulating angiogenic cells (CACs) were assessed against tobacco product use categories. In murine studies, male and female C57BL/6J, transient receptor potential ankyrin 1 (TRPA1)-null, and/or extracellular superoxide dismutase-transgenic (ecSOD-Tg) mice were exposed to mainstream cigarette smoke (MCS), e-cig aerosol, humectants, or constituent aldehydes for varying durations and concentrations. Hematological measures, plasma biomarkers, and levels of CACs were assessed. Chapter III of this dissertation describes findings from the Louisville Healthy Heart Study. E-cig or dual users showed significantly increased levels of leukocytes and of CAC-3, an early endothelial progenitor cell population, compared with never smokers. Chapter IV describes systemic and vascular changes induced by exposure to MCS, e-cig aerosol, or humectants, finding significant decreases in leukocytes after all exposures and decreases in CACs in female mice exposed to JUUL Mango aerosol. Chapter V describes effects of exposure to formaldehyde and acetaldehyde, finding that formaldehyde induces significant hematological and vascular changes. Chapter VI describes effects of exposure to acrolein and crotonaldehyde, presenting novel evidence implicating chronic crotonaldehyde exposure as a risk factor for CVD. Finally, chapter VII explores the roles of ecSOD and TRPA1 in tobacco product-related CVD, demonstrating that the effects of unsaturated aldehydes are mediated by TRPA1. This dissertation presents novel data investigating associations between CACs and e-cigs in a human cohort, examining the role of tobacco products and individual constituent aldehydes in the development of CVD, and demonstrating the role of TRPA1 in the CVD effects related to tobacco products.

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