RESUMO
OBJECTIVE: Lipid peroxides and their reactive aldehyde derivatives (LPPs) have been linked to obesity-related pathologies, but whether they have a causal role has remained unclear. Glutathione peroxidase 4 (GPx4) is a selenoenzyme that selectively neutralizes lipid hydroperoxides, and human gpx4 gene variants have been associated with obesity and cardiovascular disease in epidemiological studies. This study tested the hypothesis that LPPs underlie cardio-metabolic derangements in obesity using a high fat, high sucrose (HFHS) diet in gpx4 haploinsufficient mice (GPx4(+/-)) and in samples of human myocardium. METHODS: Wild-type (WT) and GPx4(+/-) mice were fed either a standard chow (CNTL) or HFHS diet for 24 weeks, with metabolic and cardiovascular parameters measured throughout. Biochemical and immuno-histological analysis was performed in heart and liver at termination of study, and mitochondrial function was analyzed in heart. Biochemical analysis was also performed on samples of human atrial myocardium from a cohort of 103 patients undergoing elective heart surgery. RESULTS: Following HFHS diet, WT mice displayed moderate increases in 4-hydroxynonenal (HNE)-adducts and carbonyl stress, and a 1.5-fold increase in GPx4 enzyme in both liver and heart, while gpx4 haploinsufficient (GPx4(+/-)) mice had marked carbonyl stress in these organs accompanied by exacerbated glucose intolerance, dyslipidemia, and liver steatosis. Although normotensive, cardiac hypertrophy was evident with obesity, and cardiac fibrosis more pronounced in obese GPx4(+/-) mice. Mitochondrial dysfunction manifesting as decreased fat oxidation capacity and increased reactive oxygen species was also present in obese GPx4(+/-) but not WT hearts, along with up-regulation of pro-inflammatory and pro-fibrotic genes. Patients with diabetes and hyperglycemia exhibited significantly less GPx4 enzyme and greater HNE-adducts in their hearts, compared with age-matched non-diabetic patients. CONCLUSION: These findings suggest LPPs are key factors underlying cardio-metabolic derangements that occur with obesity and that GPx4 serves a critical role as an adaptive countermeasure.
RESUMO
Prion diseases, also termed transmissible spongiform encephalopathies (TSEs), are rare and fatal neurodegenerative conditions that affect both humans and animals. Although there is increased evidence that oxidative stress plays an important role in the pathogenesis of these diseases, the direct relationship between an accumulation of abnormal prion protein (PrP(Sc)) and the occurrence of oxidative stress has not been studied. In the present study, we have investigated the cellular localization of proteins modified by lipid peroxidation end products and its correlation with PrP(Sc) accumulation in the brain of mice infected with the ME7 prion strain. Intense immunostaining of malondialdehyde (MDA)- and hydroxynonenal (HNE)-modified proteins were observed in the hippocampus of prion-infected mice. In serial section study, we found that these immunoreactivities were co-localized with glial fibrillary acidic protein (GFAP)-positive astrocytes as well as with PrP(Sc). These results clearly indicate that the heightened oxidative stress in the form of lipid peroxidation is closely associated with PrP(Sc) accumulation in astrocytes of prion-infected mice.