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-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.
Ungvari
Zoltan
Z
Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Gautam
Tripti
T
Koncz
Peter
P
Henthorn
Jim C
JC
Pinto
John T
JT
Ballabh
Praveen
P
Yan
Han
H
Mitschelen
Matthew
M
Farley
Julie
J
Sonntag
William E
WE
Csiszar
Anna
A
D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001808:Blood Vessels / Q000378:metabolism*; D001835:Body Weight; D002851:Chromatography, High Pressure Liquid; D004392:Dwarfism / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D013006:Growth Hormone / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008136:Longevity / Q000235:genetics; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020521:Stroke / Q000517:prevention & control*
D015415:Biomarkers; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D005979:Glutathione Peroxidase; D019001:Nitric Oxide Synthase; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D005721:Glutamate-Cysteine Ligase; C544143:GCLC protein, rat; D001205:Ascorbic Acid