Growth hormone and IGF-1 deficiency exacerbate high-fat diet-induced endothelial impairment in obese Lewis dwarf rats: implications for vascular aging.

Previous studies suggest that the age-related decline in circulating growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels significantly contribute to vascular dysfunction in aging by impairing cellular oxidative stress resistance pathways. Obesity in elderly individuals is increasing at alarming rates, and there is evidence suggesting that elderly individuals are more vulnerable to the deleterious cardiovascular effects of obesity than younger individuals. However, the specific mechanisms through which aging, GH/IGF-1 deficiency, and obesity interact to promote the development of cardiovascular disease remain unclear. To test the hypothesis that low circulating GH/IGF-1 levels exacerbate the pro-oxidant and proinflammatory vascular effects of obesity, GH/IGF-1-deficient Lewis dwarf rats and heterozygous control rats were fed either a standard diet or a high-fat diet (HFD) for 7 months. Feeding an HFD resulted in similar relative weight gains and increases in body fat content in Lewis dwarf rats and control rats. HFD-fed Lewis dwarf rats exhibited a relative increase in blood glucose levels, lower insulin, and impaired glucose tolerance as compared with HFD-fed control rats. Analysis of serum cytokine expression signatures indicated that chronic GH/IGF-1 deficiency exacerbates HFD-induced inflammation. GH/IGF-1 deficiency also exacerbated HFD-induced endothelial dysfunction, oxidative stress, and expression of inflammatory markers (tumor necrosis factor-α, ICAM-1) in aortas of Lewis dwarf rats. Overall, our results are consistent with the available clinical and experimental evidence suggesting that GH/IGF-1 deficiency renders the cardiovascular system more vulnerable to the deleterious effects of obesity.

Liver-specific knockdown of IGF-1 decreases vascular oxidative stress resistance by impairing the Nrf2-dependent antioxidant response: a novel model of vascular aging.

Recent studies demonstrate that age-related dysfunction of NF-E2-related factor-2 (Nrf2)-driven pathways impairs cellular redox homeostasis, exacerbating age-related cellular oxidative stress and increasing sensitivity of aged vessels to oxidative stress-induced cellular damage. Circulating levels of insulin-like growth factor (IGF)-1 decline during aging, which significantly increases the risk for cardiovascular diseases in humans. To test the hypothesis that adult-onset IGF-1 deficiency impairs Nrf2-driven pathways in the vasculature, we utilized a novel mouse model with a liver-specific adeno-associated viral knockdown of the Igf1 gene using Cre-lox technology (Igf1(f/f) + MUP-iCre-AAV8), which exhibits a significant decrease in circulating IGF-1 levels (~50%). In the aortas of IGF-1-deficient mice, there was a trend for decreased expression of Nrf2 and the Nrf2 target genes GCLC, NQO1 and HMOX1. In cultured aorta segments of IGF-1-deficient mice treated with oxidative stressors (high glucose, oxidized low-density lipoprotein, and H(2)O(2)), induction of Nrf2-driven genes was significantly attenuated as compared with control vessels, which was associated with an exacerbation of endothelial dysfunction, increased oxidative stress, and apoptosis, mimicking the aging phenotype. In conclusion, endocrine IGF-1 deficiency is associated with dysregulation of Nrf2-dependent antioxidant responses in the vasculature, which likely promotes an adverse vascular phenotype under pathophysiological conditions associated with oxidative stress (eg, diabetes mellitus, hypertension) and results in accelerated vascular impairments in aging.

Vasoprotective effects of life span-extending peripubertal GH replacement in Lewis dwarf rats.

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-1ß, 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.