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Glutathione Dysregulation, Cardiac Oxidative Stress, and Inflammation during n-6 Polyunsaturated Fatty Acid Overload

University of British Columbia

Historically dietary saturated fats were blamed for cardiovascular disease (CVD). However, lowering dietary saturated fats did not curb CVD rates and instead detrimental roles of n-6 polyunsaturated fatty acid (n-6 PUFA) which was used to substitute saturated fats have come to the forefront. My objective was to identify mechanisms leading to dietary n-6 PUFA induced CVDs using mice and cell models. Here isocaloric diets rich in n-6 PUFA or monounsaturated fatty acids (MUFA) were used in vivo or cardiac cells like cardiomyocytes and fibroblasts were incubated with n-6 PUFA or MUFA in vitro. We established that n-6 PUFA reduced glutathione (GSH), promoted oxidative stress and impaired mitochondrial function. n-6 PUFA diets also increased pro-inflammatory cytokines and impaired GSH synthesis in vivo. Removal of a primary pro-inflammatory stimulus by using mice deficient in monocyte chemotactic protein 1 (MCP-1) restored GSH and lowered inflammation in n-6 PUFA-fed MCP-1-/- mice (chapter 2). Although inflammatory biomarkers were high in n-6 PUFA incubated cells, treatment with LPS lowered murine macrophage function suggesting a dysregulated immune response. This dysregulated immune response was also reversed by increasing GSH in macrophages. These data indicate that n-6 PUFA increases inflammatory biomarkers but impairs macrophage function due to GSH depletion (chapter 3). Finally, as cell death is a major contributor to CVD, my final chapter 4 showed that under cardiac stress induced by beta-adrenergic agonist, isoproterenol, n-6 PUFA promotes necrosis, increases in cytochrome P450-induced metabolites and a reduction in DNA repair genes. Overall, these results show the key roles of GSH dysregulation in n-6 PUFA induced inflammation, which could be key novel mediator of PUFA-specific cardiotoxicity in the Western world.

Text

2017-07-17

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/62283

Biology

University of British Columbia

UBCO

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