Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response

Abstract

There is strong evidence showing that aging is associated with vascular oxidative stress, which has been causally linked to the development of cardiovascular diseases. NF-E2-related factor-2 (Nrf2) is a transcription factor, which is activated by reactive oxygen species in the vasculature of young animals leading to the upregulation of various antioxidant genes. The present study was designed to elucidate age-related changes in the homeostatic role of Nrf2-driven free radical detoxification mechanisms in the vasculature. We found that in the aorta of Fischer 344 ϫ Brown Norway rats, aging results in a progressive increase in O 2 ·Ϫ production, and downregulates protein and mRNA expression of Nrf2, which is associated with a decreased nuclear Nrf2 activity and a decrease in the Nrf2 target genes NAD(P)H:quinone oxidoreductase 1, ␥-glutamylcysteine synthetase, and heme oxygenase-1. There was an inverse relationship between vascular expression of Nrf2 target genes and agerelated increases in the expression of the NF-B target genes ICAM-1 and IL-6, which was significant by regression analysis. In cultured aorta segments of young (3 mo old) rats treatment with H 2O2 and high glucose significantly increases nuclear translocation of Nrf2 and upregulates the expression of Nrf2 target genes. In contrast, in cultured aorta segments of aged (24 mo old) rats, the induction of Nrf2-dependent responses by H 2O2 and high glucose are blunted. High glucose-induced vascular oxidative stress was more severe in aortas of aged rats, as shown by the significantly increased H 2O2 production in these vessels, compared with responses obtained in aortas from young rats. Moreover, we found that aging progressively increases vascular sensitivity to the proapoptotic effects of H 2O2 and high glucose treatments. Taken together, aging is associated with Nrf2 dysfunction in the vasculature, which likely exacerbates age-related cellular oxidative stress and increases sensitivity of aged vessels to oxidative stressinduced cellular damage.senescence; apoptosis; oxidative stress resistance; vascular injury THE OXIDATIVE STRESS THEORY of aging postulates that increased production of reactive oxygen species (ROS) with age induces a variety of macromolecular oxidative modifications and that accumulation of such oxidative damage is a major causal factor in organismic senescence. Although there is currently much debate over the importance of increased cellular oxidative stress in regulation of life span (4, 29), there is a consensus that increased ROS levels importantly contribute to the development of age-associated diseases (68). There is strong evidence that oxidative stress develops with age in the arterial system both in humans (19 -21, 25, 28) and laboratory animals (16,24,26,44,61). Increased production of ROS in the aged vasculature results in endothelial dysfunction and promotes the development of atherosclerotic vascular diseases (including myocardial infarction, stroke, vascular dementia), which are responsible for the majority of agerelate...

Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging

“…The IGF-1 dependent mechanisms responsible for impairment of endothelial angiogenic capacity likely also include dysregulation of Nrf2, a newly discovered regulator of endothelial angiogenic processes (Valcarcel-Ares et al 2012). This concept is supported by the findings that aging is associated with Nrf2 dysfunction in endothelial cells (Ungvari et al 2011a;Ungvari et al 2011b) and that IGF-1 deficiency exacerbates Nrf2 dysfunction (Bailey-Downs et al 2012a), mimicking the aging phenotype.…”

“…Figure 6 shows the effects of IGF-1 deficiency and hypertension on the hippocampal expression of the angiogenesis inhibitors Serpinf1 (PEDF), f i b u l i n -5 ( F b l n 5 ) ( S u l l i v a n e t a l . 2 0 0 7 ) , thromhospondin-1 (Thbs1) (Lawler 2002), Thbs2 (Volpert et al 1995), the potent anti-angiogenic chemokine platelet factor 4 (Pf4) (Bikfalvi 2004); vasohibin-1 (Vash1), which is a newly recognized (Takano et al 2014), Adamts1 ("a disintegrin and metalloproteinase with thrombospondin motifs 1"), which inhibits angiogenesis (Lee et al 2006) by suppressing endothelial cell proliferation; Col18a1, whose expression level impacts endostatin signaling and endothelial angiogenic capacity (Li and Olsen 2004) (endostatin, a potent inhibitor of angiogenesis, is a 20-kDa C-terminal fragment derived from type XVIII collagen); semaphorin-3F (Sema3f) (Ungvari et al 2011b;Frisbee et al 2007); tenomodulin (Tnmd) (Oshima et al 2003); brainspecific angiogenesis inhibitor 1 (Bai1; also known as adhesion G protein-coupled receptor B1 [ADGRB1]) (Nishimori et al 1997); chromogranin A (Chga), which encodes the precursor to several angiogenesis inhibitor peptides including vasostatin-1 and vasostatin-2 (Helle and Corti 2015) and maspin ("mammary serine protease inhibitor"; encoded by the Serpinb5 gene (Qin and Zhang 2010). Figure 7 shows the expression of Tnfa, whose overproduction has been causally linked to microvascular rarefaction (Frisbee et al 2014); Tgfb1, which regulates multiple aspects of the angiogenic process and contributes to hypertension-induced microvascular rarefaction in the heart (Koitabashi et al 2011); Tgfa; angiogenin (Ang, also known as ribonuclease 5), which is a potent stimulator of angiogenesis and an inhibitor of endothelial apoptosis; Edil3 (EGF-like repeats and discoidin Ilike domains 3), which encodes a glycoprotein secreted by endothelial cells that regulates apoptosis, cell migration (Zhong et al 2003) and induces cerebral angiogenesis in mice (Fan et al 2008); midkine (Mdk, also known as neurite growth-promoting factor 2 or NEGF2), which is a pleiotropic growth factor regulating cell proliferation, cell migration and promoting angiogenesis (Mashour et al 2001 [HB-GAM]), which is a pro-angiogenic growth factor that is structurally related to midkine and whose expression in the adult brain is induced by ischemia; Tymp (thymidine phosphorylase, also known as platelet-derived endothelial cell growth factor [ECGF1], which stimulates endothelial cell proliferation and induces angiogenesis in the brain …”

Insulin-like growth factor 1 deficiency exacerbates hypertension-induced cerebral microhemorrhages in mice, mimicking the aging phenotype

“…This concept is supported by recent findings showing that age‐related exacerbation of hypertension‐induced MMP activation can be abolished by antioxidative treatments (Toth et al ., 2015b). Increased hypertension‐induced oxidative stress in aged arteries has been attributed to upregulation of NOX oxidases, increased mitochondrial ROS generation, and impaired Nrf2‐dependent antioxidant defense mechanisms (Ungvari et al ., 2011a,b; Springo et al ., 2015; Toth et al ., 2015b). There is evidence that inhibition of ROS synthesis by these sources can prevent development of CMHs in aging (Toth et al ., 2015b).…”

An increased need for dietary cysteine in support of glutathione synthesis may underlie the increased risk for mortality associated with low protein intake in the elderly

“…In this regard, there is considerable evidence that glutathione synthesis and glutathione tissue levels tend to decline in rodents and humans as they age (Suh et al 2004a;Rebrin and Sohal 2008;Rebrin et al 2007;Droge et al 2006;Sekhar et al 2011;Wang et al 2003;Lean et al 2005). This appears to reflect, in turn, an age-related decline in expression and function of the Nrf2 transcription factor (Suh et al 2004a;Suh et al 2004b;Ungvari et al 2011;Shih and Yen 2007). Nrf2 promotes transcription of a wide array of enzymes which combats oxidative stress and aids the detoxification of mutagenic electrophiles; among these is the ratelimiting enzyme for glutathione synthesis, glutamate cysteine lyase (GCL) (Wild et al 1999;Lee and Surh 2005).…”

“…Nrf2 promotes transcription of a wide array of enzymes which combats oxidative stress and aids the detoxification of mutagenic electrophiles; among these is the ratelimiting enzyme for glutathione synthesis, glutamate cysteine lyase (GCL) (Wild et al 1999;Lee and Surh 2005). Why Nrf2 expression declines with age remains mysterious; a concurrent upregulation of its functional antagonist Keap1 may also contribute to a loss of Nrf2 activity in the elderly (Ungvari et al 2011). The agerelated decline in GCL activity may also reflect a structural alteration in this enzyme, as there is one report that the affinity of this enzyme for its rate-limiting substrate cysteine declines in aging rat liver (Suh et al 2004a).…”