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

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.Arts and Sciences, Irving K. Barber School of (Okanagan)Biology, Department of (Okanagan)Graduat