Roles of Macrophage Mitochondrial Oxidative Stress and Mitochondrial Fission in Atherosclerosis

Electron transportation (ET) coupled with oxidative phosphorylation (OXPHOS) in the mitochondria produces limited, physiologic levels of reactive oxygen species (ROS). While this process is adaptive under normal conditions, excessive mitochondrial oxidative stress (mitoOS) has been correlated with a number of diseases, including atherosclerotic vascular disease in humans. However, definitive evidence of causation and cell-specific pro-atherogenic mechanisms of mitoOS require further investigation. The high level of interest in this topic, the human relevance, and the potential therapeutic implications prompted us to explore causation and mechanism with a focus on the key inflammatory cell type in atherosclerosis, the macrophage (Chapter 2). For this purpose, we used a recently described model, the mitochondrial catalase (mCAT) transgenic mouse, that decreases mitoOS in vivo. Normally, glutathione perioxidase is the endogenous mitochondrial enzyme that catalyzes the reduction of H2O2 and prevents its conversion into the most detrimental ROS hydroxyl nitrites. Catalase can carry out this role in peroxisomes, where it is exclusively located. The mCAT transgenic mouse expresses human c