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.
Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Lora C
LC
Bailey-Downs
Matthew
M
Mitschelen
Danuta
D
Sosnowska
Peter
P
Toth
John T
JT
Pinto
Praveen
P
Ballabh
M Noa
MN
Valcarcel-Ares
Julie
J
Farley
Akos
A
Koller
Jim C
JC
Henthorn
Caroline
C
Bass
William E
WE
Sonntag
Zoltan
Z
Ungvari
Anna
A
Csiszar
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D017209:Apoptosis; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D006861:Hydrogen Peroxide / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis*; D018384:Oxidative Stress; D046509:Tissue Culture Techniques
D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C519530:insulin-like growth factor-1, mouse; C099252:oxidized low density lipoprotein; D007334:Insulin-Like Growth Factor I; D006861:Hydrogen Peroxide; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D005721:Glutamate-Cysteine Ligase