The Use of Gpx4 Knockout Mice and Transgenic Mice to Study the Roles of Lipid Peroxidation in Diseases and Aging

Abstract

Lipid peroxidation, a primary event of oxidative stress, is considered to be important in disease pathogenesis and aging. Glutathione peroxidase 4 (Gpx4) is an antioxidant defense enzyme that can directly reduce lipid hyproperoxides in membrane lipids. Several Gpx4 knockout mouse models and Gpx4 transgenic mouse models have been generated over the past 7 years, and data collected from those models indicate that Gpx4 plays an essential role in protecting against lipid peroxidation. Because Gpx4 knockout mice and Gpx4 transgenic mice show increased lipid peroxidation and decreased lipid peroxidation, respectively, those models were used to investigate the roles of lipid peroxidation in aging and disease. For example, lifespan studies showed that Gpx4 heterozygous knockout mice and Gpx4 transgenic mice altered lifespans, indicating that mild change in lipid peroxidation does not affect aging. However, studies using Gpx4 transgenic and knockout models showed that overexpression of Gpx4 protected against Aβ toxicity and that deficiency of Gpx4 resulted in increased amyloidogenesis in brain, indicating that lipid peroxidation is important in the pathogenesis of Alzheimer’s disease. Studies using Gpx4 transgenic mice also showed that overexpression of Gpx4 reduced atherosclerosis and attenuated cardiac ischemia/reperfusion injury, suggesting that lipid peroxidation is important in cardiovascular disease. Therefore, Gpx4 knockout and transgenic mouse models are useful in ­dissecting the in vivo roles of lipid peroxidation in diseases and aging.