ascorbic-acid and Dwarfism

In humans, growth hormone deficiency (GHD) and low circulating levels of insulin-like growth factor 1 (IGF-1) significantly increase the risk for cerebrovascular disease. Genetic growth hormone (GH)/IGF-1 deficiency in Lewis dwarf rats significantly increases the incidence of late-life strokes, similar to the effects of GHD in elderly humans. Peripubertal treatment of Lewis dwarf rats with GH delays the occurrence of late-life stroke, which results in a significant extension of life span. The present study was designed to characterize the vascular effects of life span-extending peripubertal GH replacement in Lewis dwarf rats. Here, we report, based on measurements of dihydroethidium fluorescence, tissue isoprostane, GSH, and ascorbate content, that peripubertal GH/IGF-1 deficiency in Lewis dwarf rats increases vascular oxidative stress, which is prevented by GH replacement. Peripubertal GHD did not alter superoxide dismutase or catalase activities in the aorta nor the expression of Cu-Zn-SOD, Mn-SOD, and catalase in the cerebral arteries of dwarf rats. In contrast, cerebrovascular expression of glutathione peroxidase 1 was significantly decreased in dwarf vessels, and this effect was reversed by GH treatment. Peripubertal GHD significantly decreases expression of the Nrf2 target genes NQO1 and GCLC in the cerebral arteries, whereas it does not affect expression and activity of endothelial nitric oxide synthase and vascular expression of IGF-1, IGF-binding proteins, and inflammatory markers (tumor necrosis factor alpha, interluekin-6, interluekin-1β, inducible nitric oxide synthase, intercellular adhesion molecule 1, and monocyte chemotactic protein-1). In conclusion, peripubertal GH/IGF-1 deficiency confers pro-oxidative cellular effects, which likely promote an adverse functional and structural phenotype in the vasculature, and results in accelerated vascular impairments later in life.

Topics: Animals; Ascorbic Acid; Biomarkers; Blood Vessels; Body Weight; Chromatography, High Pressure Liquid; Dwarfism; Endothelium, Vascular; Glutamate-Cysteine Ligase; Glutathione Peroxidase; Growth Hormone; Insulin-Like Growth Factor I; Longevity; NAD(P)H Dehydrogenase (Quinone); Nitric Oxide Synthase; Oxidative Stress; Phenotype; Rats; Rats, Inbred Lew; Reverse Transcriptase Polymerase Chain Reaction; Stroke

Factors affecting longevity are complex and poorly understood. We have recently found that Ames dwarf mice (df/df), which are deficient in growth hormone (GH), prolactin, and thyroid-stimulating hormone, live significantly longer than their normal siblings whereas transgenic mice that overexpress GH exhibit reduced life-spans and various indices of premature aging. The production of reactive oxygen species increases with aging and is associated with DNA damage to the tissues. However, several cellular oxygen scavenging/detoxifying systems exist that improve the antioxidative defense capacity of cells. We evaluated the activity of enzymes involved in this defense system in liver, kidney, and heart tissue from dwarf, phosphoenol-pyruvate carboxykinase-bovine GH transgenic, and corresponding groups of normal mice. Liver glutathione and ascorbate levels were lower (p < 0.0025) in dwarf animals compared to normal and GH transgenic mice. By contrast, the level of catalase activity, which detoxifies hydrogen peroxide, in dwarf liver and kidney was significantly higher when compared to the other groups. Animals deficient in GH (dwarf) live longer and exhibit enzyme activities and levels that may combat oxidative stress more efficiently than normal mice and those overexpressing GH.

Topics: Aging; Animals; Antioxidants; Ascorbic Acid; Catalase; Dwarfism; Free Radicals; Glucosephosphate Dehydrogenase; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Growth Hormone; Kidney; Liver; Mice; Mice, Transgenic; Oxidation-Reduction; Oxidoreductases