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Copp, Amanda

University of British Columbia

Cardiovascular disease (CVD) is a leading cause of premature mortality. Fibrosis of the heart is a major contributor to chronic CVD pathology. Oxidative stress resulting from, an imbalance of oxidizers and antioxidants, is a major player in the development of CVD. Both exposure to heavy metals, like lead (Pb), and the overconsumption of omega-6 polyunsaturated fatty acids (PUFAs) have separately been linked with increased oxidative stress and fibrosis. Regulatory bodies have deemed certain blood Pb levels as acceptable, but Pb levels are misrepresented, and evidence shows that these ‘allowable’ levels are unsafe. Given the preponderance of omega-6 PUFA and Pb in the Canadian food supply, this investigates the interactions between Pb and fatty acids (FAs) on markers of cellular oxidative stress and fibrosis work for the first time. Two murine cell models, NIH-3T3 fibroblasts and RAW 264.7 macrophages, were used as models of fibrosis formation and inflammation respectively were used. The PUFA, linoleic acid (LA) and a saturated fatty acid, palmitic acid (PA) were used to study cellular absorption parameters of Pb. In chapter 2, dose-response studies were conducted to determine what levels of Pb, could keep cells alive and allow them to show stress responses over 24 hours. Chapter 3 investigated Pb absorption using an intracellular Pb-specific fluorescent probe and found that Pb absorption in fibroblasts and macrophages was decreased by the presence of both FA. It was further shown that exposure of RAW 264.7 macrophage cells to 5uM Pb and 25uM LA induced more Pb absorption than 5uM Pb and 25uM PA. This could indicate that omega-6 PUFA can promote Pb absorption greater than a saturated fatty acid. Chapter 4 concludes with investigation into the gene expression of various antioxidizing genes and membrane proteins that transport Pb, both of which can play a critical role in oxidative stress and fibrosis. Overall, these results give an initial understanding of Pb and FA interactions at the cellular level, in hopes that this provides the initial step in justifying the need of continued investigation into the synergistic roles of low-level Pb exposure and dietary fats towards cellular stress and CVD.

Text

2024-06-17

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/88473

Biochemistry and Molecular Biology

University of British Columbia

UBCO

http://creativecommons.org/licenses/by-nc-nd/4.0/