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

Lora C. Bailey-Downs, Matthew Mitschelen, Danuta Sosnowska, Peter Toth, John T. Pinto, Praveen Ballabh, M. Noa Valcarcel-Ares, Julie Farley, Akos Koller, Jim C. Henthorn, Caroline Bass, William E. Sonntag, Zoltan Ungvari, Anna Csiszar

Research output: Contribution to journalReview article

101 Scopus citations

Abstract

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 H2O2), 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.

Original languageEnglish (US)
Pages (from-to)313-329
Number of pages17
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume67 A
Issue number4
DOIs
StatePublished - Apr 1 2012
Externally publishedYes

Keywords

  • endocrine
  • vascular aging

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology

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    Bailey-Downs, L. C., Mitschelen, M., Sosnowska, D., Toth, P., Pinto, J. T., Ballabh, P., Valcarcel-Ares, M. N., Farley, J., Koller, A., Henthorn, J. C., Bass, C., Sonntag, W. E., Ungvari, Z., & Csiszar, A. (2012). Liver-specific knockdown of IGF-1 decreases vascular oxidative stress resistance by impairing the Nrf2-dependent antioxidant response: A novel model of vascular aging. Journals of Gerontology - Series A Biological Sciences and Medical Sciences, 67 A(4), 313-329. https://doi.org/10.1093/gerona/glr164