Cardiac nitric oxide synthases are elevated in dietary copper deficiency

Saari, Jack T.; Wold, Loren E.; Duan, Jiaqi; Ren, Jun; Carlson, Hanqian L.; Bode, Ann M.; Lentsch, Alex B.; Zeng, Huawei; Schuschke, Dale A.

doi:10.1016/j.jnutbio.2006.07.006

Cited by 8 publications

(7 citation statements)

References 42 publications

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“…Others have previously reported enhanced 3-nitrotyrosine staining in neutral tube tissue of copper deficient embryos (Beckers-Trapp et al, 2006). Furthermore, cardiac tissue from Cu deficient rats was recently shown to have increased NOS activity and expression levels (Saari et al, 2007). Cu− rat pups in the current experiments exhibited marked cardiac hypertrophy suggesting that severe Cu deficiency in cardiac tissue was evident (data not shown).…”

Section: Discussionsupporting

confidence: 49%

Copper deficiency results in AMP-activated protein kinase activation and acetylCoA carboxylase phosphorylation in rat cerebellum

Gybina

Prohaska

2008

Brain Research

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Copper (Cu) deficiency impairs cerebellar development including biosynthetic processes like myelination and synaptogenesis. The activity of cerebellar mitochondrial cuproenzyme cytochrome c oxidase is markedly lower in Cu deficient rat pups and is accompanied by higher lactate levels indicating mitochondrial inhibition. Cu deficiency impaired energy metabolism is thought to contribute to developmental delays, but specific mechanisms linking these phenomena have remained unexplored. AMP activated protein kinase (AMPK) is a cellular energy sensor that is activated during mitochondrial inhibition and shuts down biosynthetic processes to help conserve cellular ATP levels. Activated AMPK phosphorylates and inhibits acetyl CoA carboxylase (ACC), the first enzyme in fatty acid biosynthesis. We hypothesize AMPK is activated and ACC inhibited in Cu deficient cerebella. Perinatal copper deficiency was studied in young rats in rapidly frozen cerebella. Compared to copper adequate (Cu+) pups, copper deficient (Cu−) pups were hypothermic, had lower brain copper levels and markedly higher cerebellar lactate. Concentration of phosphorylated AMPK (pAMPK), indicating AMPK activation, was robustly higher in Cu− cerebella of rat pups at two ages and in two separate experiments. Compared to Cu+ cerebella, pACC content was significantly higher in all Cu− samples. Mechanisms leading to AMPK activation remain elusive. Higher AMP/ATP ratios and increased reactive nitrogen species (RNS) can lead to AMPK activation. ATP and AMP concentrations were unaltered and nitric oxide metabolites and 3-nitrotyrosine peptide levels remained unchanged in Cu− cerebella. AMPK activation may explain how ATP levels can be maintained even with a severe mitochondrial loss of CCO function.

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Section: Discussionsupporting

confidence: 49%

Copper deficiency results in AMP-activated protein kinase activation and acetylCoA carboxylase phosphorylation in rat cerebellum

Gybina

Prohaska

2008

Brain Research

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“…It is important to note that Cu status seems to modulate NO metabolism differently depending on the tissue. In contrast to Cu deficient yolk sacs, hearts from Cu deficient adult rats have increased expression of iNOS and eNOS and produce large amounts of NO [50,51] which may contribute to Cu deficiency-induced cardiomyopathy and heart failure.…”

Section: Discussionmentioning

confidence: 99%

Low nitric oxide: a key factor underlying copper-deficiency teratogenicity

Yang

Keen

Lanoue

et al. 2007

Free Radical Biology and Medicine

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Copper (Cu)-deficiency-induced teratogenicity is characterized by major cardiac, brain, and vascular anomalies; however, the underlying mechanisms are poorly understood. Cu deficiency decreases superoxide dismutase activity and increases superoxide anions, which can interact with nitric oxide (NO), reducing the NO pool size. Given the role of NO as a developmental signaling molecule, we tested the hypothesis that low NO levels, secondary to Cu deficiency, represent a developmental challenge. Gestation day 8.5 embryos from Cu-adequate (Cu+) or Cu-deficient (Cu-) dams were cultured for 48 h in Cu+ or Cu- medium, respectively. We report that NO levels were low in conditioned medium from Cu-/Cu- embryos and yolk sacs, compared to Cu+/Cu+ controls under basal conditions and with NO synthase (NOS) agonists. The low NO production was associated with low endothelial NOS phosphorylation at serine 1177 and cyclic guanosine-3',5'-monophosphate (cGMP) concentrations in the Cu-/Cu- group. The altered NO levels in Cu-deficient embryos are functionally significant, as the administration of the NO donor DETA/NONOate increased cGMP and ameliorated embryo and yolk sac abnormalities. These data support the concept that Cu deficiency limits NO availability and alters NO-dependent signaling, which contributes to abnormal embryo and yolk sac development.

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“…Cardiomyopathy induced by Cu deficiency during pre‐, peri‐ and postnatal periods is well established in experimental animals [92–94]. Cu deficient hearts exhibit concentric hypertrophy, fibrosis, myofibril derangement, contractile and electrophysiological dysfunction, aneurysms, and eventual heart failure [95–97]. Offspring from dams fed Cu deficient diets from pregnancy through lactation have low cardiac cytochrome c oxidase activity, high hydrogen peroxide levels, and cardiomyocyte structural damage, which persists despite long‐term Cu repletion initiated at weaning [98].…”

Section: Copper Deficiency and Pregnancy Outcomementioning

confidence: 99%

“…In contrast to low NO metabolism in the Cu deficient embryo and yolk sac, the adult Cu deficient heart is characterized by elevated NOS activity, and iNOS and eNOS protein expression [96]. Moreover, Cu deficient hearts are characterized by a compromised oxidant defense system and increased nitrotyrosine [96, 110]. Interestingly, altered NO metabolism occurs in humans and animals that lack the Cu transporter, ceruloplasmin (Cp) [173].…”

Section: Potential Mechanismsmentioning

confidence: 99%

Influence of copper on early development: Prenatal and postnatal considerations

et al. 2010

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Copper (Cu) is an essential nutrient whose requirement is increased during pregnancy and lactation. These represent times of critical growth and development, and the fetus and neonate are particularly vulnerable to deficiencies of this nutrient. Genetic mutations that predispose the offspring to inadequate stores of Cu can be life threatening as is observed in children with Menkes disease. During the last decade, severe Cu deficiency, once thought to be a rare condition, has been reported in the literature at an increasing frequency. Secondary Cu deficiencies can be induced by a variety of ways such as excessive zinc or iron intake, certain drugs, and bariatric surgery. Premature and low birth weight infants can be born with low Cu stores. A number of mechanisms can contribute to the teratogenicity of Cu including decreased activity of select cuproenzymes, increased oxidative stress, decreased nitric oxide availability, altered iron metabolism, abnormal extracellular matrix protein crosslinking, decreased angiogenesis and altered cell signaling among others. The brain, heart, and vessels as well as tissues such as lung, skin and hair, and systems including the skeletal, immune, and blood systems, are negatively affected by suboptimal Cu during development. Additionally, persistent structural, biochemical, and functional adverse effects in the offspring are noted even when Cu supplementation is initiated after birth, supporting the concept that adequate Cu nutriture during pregnancy and lactation is critical for normal development. Although Cu-containing IUDs are an effective method for increasing intrauterine Cu concentrations and for reducing the risk of pregnancy, high amounts of dietary Cu are not thought to represent a direct developmental risk.

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Cardiac nitric oxide synthases are elevated in dietary copper deficiency

Cited by 8 publications

References 42 publications

Copper deficiency results in AMP-activated protein kinase activation and acetylCoA carboxylase phosphorylation in rat cerebellum

Copper deficiency results in AMP-activated protein kinase activation and acetylCoA carboxylase phosphorylation in rat cerebellum

Low nitric oxide: a key factor underlying copper-deficiency teratogenicity

Influence of copper on early development: Prenatal and postnatal considerations

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