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The role of glutathione peroxidase 1 in the heart following high fat feeding

University of British Columbia

Over the last century, the composition of dietary fats has changed in Western countries leading to an increased ratio of n-6:n-3 polyunsaturated fatty acid (PUFA) consumption. It has been suspected that this altered ratio may contribute to the increase in incidence of cardiovascular diseases in Western countries. One of the classical ways how diet can impact diseases is through increasing oxidative stress. Previous studies have shown that linoleic acid (LA), a common dietary n-6 PUFA, is able to induce oxidative stress. Oxidative stress in the heart can be mitigated by antioxidants. In this regard, glutathione peroxidase 1 (GPx1) is an important antioxidant involved in protecting the heart. My project was to investigate the role of GPx1, in protecting the heart especially following a high n-6 fatty acid Western diet. The first objective was to investigate the effects of high fat diets in vivo in GPx1 deficient mouse hearts (Chapter 1). At the onset, we determined that GPx1⁺/- mouse hearts had lower mitochondrial copy number indicating metabolic abnormality. Upon feeding of various diets, we established that a GPx1 heterozygous KO does not affect linoleic acid induced cardiotoxicity in mice Further, GPx1⁺/- mouse hearts did not have reduced cardiac function, thereby indicating that even in reduced amounts, GPx1 is able to provide protection. Regarding antioxidants the GPx1+/- mouse hearts had upregulated gene expression of other antioxidants such as GPx4, superoxide dismutase (SOD) 1, SOD2, and catalase when compared to the wildtype control mice, indicating that alternate antioxidants did maintain antioxidant status in these mice. The second objective was to investigate the interactions between GPx1 and fatty acids in vitro on antioxidant regulation in H9c2 cardiomyocytes, one of the main heart cell types, in causing cell death (Chapter 2). GPx1 overexpression increased cellular uptake of neutral red indicating higher cell number. However, with incubation with fatty acids, we found that GPx1 overexpression increased caspase 3/7 activity with lower LDH release, thereby indicating a more controlled mode of cell death. Furthermore, we determined that GPx1 overexpressed cells incubated with linoleic acid, and not oleic acid, had increased glutathione, possibly an adjustment to cope with the increased oxidative stress that occurs after n-6 PUFA exposure. Overall, these results contribute to understanding the role of GPx1 in the heart under various dietary fatty acids.

Text

2019-10-21

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/71987

Biochemistry and Molecular Biology

University of British Columbia

UBCO

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