Thermosensitive phenotype of transgenic mice overproducing human glutathione peroxidases.

Abstract

Exposure of humans and other mammals to hyperthermic conditions elicits many physiological responses to stress in various tissues leading to profound injuries, which eventually result in death. It has been suggested that hyperthermia may increase oxidative stress in tissues to form reactive oxygen species harmful to cellular functions. By using transgenic mice with human antioxidant genes, we demonstrate that the overproduction of glutathione peroxidase (GP, both extracellular and intracellular) leads to a thermosensitive phenotype, whereas the overproduction of Cu,Znsuperoxide dismutase has no effect on the thermosensitivity of transgenic mice. Induction of HSP70 in brain, lung, and muscle in GP transgenic mice at elevated temperature was significantly inhibited in comparison to normal animals. Measurement of peroxide production in regions normally displaying induction of HSP70 under hyperthermia revealed high levels of peroxides in normal mice and low levels in GP transgenic mice. There was also a significant difference between normal and intracellular GP transgenic mice in level of prostaglandin E2 in hypothalamus and cerebellum. These data suggest direct participation of peroxides in induction of cytoprotective proteins (HSP70) and cellular mechanisms regulating body temperature. GP transgenic mice provide a model for studying thermoregulation and processes involving actions of hydroxy and lipid peroxides in mammals.

Impairment of synaptic transmission by transient hypoxia in hippocampal slices: Improved recovery in glutathione peroxidase transgenic mice

“…A decrease in peroxide production associated with GPx overexpression had been demonstrated in these Tg mice (13), thus lending strong support for a major role of peroxide formation in cellular injury mediated by transient ischemia. It should be noted, however, that GPx overexpression in these mice may be detrimental to various physiological processes, including the ability to induce heat shock proteins in response to elevated temperature (13). It will therefore be of interest to compare the responses of our Tg-GPx mice to focal cerebral ischemia, because these animals seem to express lower levels of human GPx.…”

“…Recently, Tg mice overexpressing GPx1 were found to be partially resistant to myocardial ischemia (11) and, more recently, to brain ischemia (12). However, these Tg mice, with high levels of GPx in the brain, may show abnormal physiological responses, such as a thermosensitive phenotype (13). On the other hand, it is not known whether the protective effects observed at the morphological level in response to focal cerebral ischemia (12) are also exerted at the functional level.…”

Inflammatory Response and Glutathione Peroxidase in a Model of Stroke

“…The generation of transgenic mice with human GPx1 genes in a C57BL/ 6 ϫ CBA/J background was previously reported (4,7). The mouse line GPE23 (containing 200 copies of the human GPx1 gene) was used for these studies.…”

“…B oth animal studies and clinical data indicate that brain ischemia/reperfusion (I/R) 4 injury is a complex, multistage process. It is initiated by the immediate damage caused by hypoxia as well as by the return of oxygenated blood, which injures the microvasculature (1).…”

“…To address the role of ROS, particularly those sensitive to intracellular glutathione peroxidase (GPx1) activity in brain I/R, we used transgenic mice overexpressing human GPx1 (4). Experiments with GPx1 transgenic mice subjected to intraluminal blockade of the middle cerebral artery (MCA) as a model system have shown that they are protected against brain I/R damage (5).…”