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

Zoltan Ungvari, Tripti Gautam, Peter Koncz, Jim C. Henthorn, John T. Pinto, Praveen Ballabh, Han Yan, Matthew Mitschelen, Julie Farley, William E. Sonntag, Anna Csiszar

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1145-1156
Number of pages12
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume65 A
Issue number11
DOIs
StatePublished - Nov 2010
Externally publishedYes

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Growth Hormone
Somatomedins
Blood Vessels
Cerebral Arteries
Catalase
Superoxide Dismutase
Stroke
Isoprostanes
Insulin-Like Growth Factor Binding Protein 1
Cerebrovascular Disorders
Human Growth Hormone
Chemokine CCL2
Nitric Oxide Synthase Type III
Nitric Oxide Synthase Type II
Intercellular Adhesion Molecule-1
Life Expectancy
Aorta
Oxidative Stress
Tumor Necrosis Factor-alpha
Fluorescence

Keywords

  • GH deficiency
  • GH replacement
  • IGF-1 deficiency
  • Oxidative stress
  • Vasoprotection

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology
  • Medicine(all)

Cite this

Vasoprotective effects of life span-extending peripubertal GH replacement in lewis dwarf rats. / Ungvari, Zoltan; Gautam, Tripti; Koncz, Peter; Henthorn, Jim C.; Pinto, John T.; Ballabh, Praveen; Yan, Han; Mitschelen, Matthew; Farley, Julie; Sonntag, William E.; Csiszar, Anna.

In: Journals of Gerontology - Series A Biological Sciences and Medical Sciences, Vol. 65 A, No. 11, 11.2010, p. 1145-1156.

Research output: Contribution to journalArticle

Ungvari, Z, Gautam, T, Koncz, P, Henthorn, JC, Pinto, JT, Ballabh, P, Yan, H, Mitschelen, M, Farley, J, Sonntag, WE & Csiszar, A 2010, 'Vasoprotective effects of life span-extending peripubertal GH replacement in lewis dwarf rats', Journals of Gerontology - Series A Biological Sciences and Medical Sciences, vol. 65 A, no. 11, pp. 1145-1156. https://doi.org/10.1093/gerona/glq147
Ungvari, Zoltan ; Gautam, Tripti ; Koncz, Peter ; Henthorn, Jim C. ; Pinto, John T. ; Ballabh, Praveen ; Yan, Han ; Mitschelen, Matthew ; Farley, Julie ; Sonntag, William E. ; Csiszar, Anna. / Vasoprotective effects of life span-extending peripubertal GH replacement in lewis dwarf rats. In: Journals of Gerontology - Series A Biological Sciences and Medical Sciences. 2010 ; Vol. 65 A, No. 11. pp. 1145-1156.
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abstract = "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.",
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