Biomedical Sciences ETDs

Publication Date

Fall 11-14-2016

Abstract

Young, healthy smokers have an increased risk of developing cardiovascular disease (CVD), but early identification of these individuals can prevent progression to more severe cardiovascular diseases like atherosclerosis, stroke, and heart attacks. However, methods developed to detect cardiovascular disease in its early stages are limited and very costly. The goal of this project is to identify biomarkers that can be tested in a single blood draw from smokers in order to both assess their risk of developing cardiovascular disease and identify possible therapeutic targets to prevent disease progression.

The long term goals of this project are to investigate the association between CVD risk, aryl hydrocarbon receptor (AHR) activity, and polyunsaturated fatty acids (PUFAs) in smokers, and to elucidate the mechanisms of their contribution to cigarette smoke (CS)-induced vascular dysfunction.

We have shown that AHR activity and α-linolenic acid (ALA, an n-3 PUFA) are potential biomarkers for CVD risk in young, healthy smokers. It is possible that the biomarkers identified in young, healthy smokers may serve not only as early identification of individuals most at risk of developing CVD, but also as biomarkers for future CVD risk in smokers with early stage CVD. As expected, the biomarkers identified in young, healthy smokers are different from biomarkers identified in older smokers with hypertension, a risk factor for development of CVD.

In a second study conducted in subjects between 40 and 70 yrs old with physician-diagnosed hypertension. We found that ALA, which we previously demonstrated to predict flow-mediated dilation (FMD) in young, healthy smokers, is not associated with atherosclerotic cardiovascular disease (ASCVD) risk in smokers with preexisting hypertension. Nonetheless, we found that 13,14-dihydroxydocosapentaenoic acid (DiHDPA), along with 11- and 20-hydroxyeicosatetraenoic acid (HETE), predict ASCVD risk in smokers, whereas 14,15-epoxyeicosatetraenoic acid (EEQ), 13,14- and 16,17-epoxyeicosatetraenoic acid (EDP), and 16,17-DiHDPA predict ASCVD risk in non-smokers. These results suggest that the fatty acids identified in this study may be used to predict CVD risk in subjects with pre-existing CVD risk factors.

In order to investigate the specific mechanisms through which n-3 PUFAs protect against CS-induced vascular dysfunction in humans, we generated a mouse model of CS-exposure that resembles what is seen in young, healthy smokers. We made the novel observation that although CS impairs nitric oxide (NO)-dependent flow-mediated dilation (FMD), an n-3 PUFA diet restores FMD by increasing NO-independent dilation. We also found that the vasoprotective properties of n-3 PUFAs may be, at least in part, due to its antioxidant properties and reduction of Cyp1a1 expression.

These studies will contribute to the understanding of CVD progression in smokers and the mechanisms of how n-3 PUFAs protect against CS-induced CVD. In addition, these findings will continue to contribute to the development of biomarkers to detect patients at high CVD risk while they are at early stages of the disease.

Keywords

Cigarette smoke, cardiovascular disease, omega-3 polyunsaturated fatty acids, oxidative stress, endothelial dysfunction

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Mary K. Walker, PhD

Second Committee Member

Matthew J Campen, PhD

Third Committee Member

Nancy L. Kanagy, PhD

Fourth Committee Member

Joe Anderson, PharmD

Download

Share

COinS