Mechanisms of Neuroprotection from Hypoxia-Ischemia (HI) Brain Injury by Up-regulation of Cytoglobin (CYGB) in a Neonatal Rat Model

Tian, Shufeng; Yang, Haiying; Xiao, Dan-ping; Huang, Yuejun; He, Gu-yu; Ma, Hai-Ran; Xia, Fang; Xue-chuan, Shi

doi:10.1074/jbc.m112.428789

Cited by 47 publications

(40 citation statements)

References 80 publications

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“…The high degree of co-expression with HO-1 is notable as HO-1 is an oxidative stress-inducible protein and enzymatic degradation of heme leads to the production of iron, biliverdin (an antioxidant) and CO (34). Cygb may therefore either be a heme substrate for HO-1 or alternatively, Cygb may, in these HO-1-expressing neurons, regulate the level of the gas-neurontransmitter CO produced by HO-1 in a similar way to that proposed for NO (18,19,21).…”

Section: Discussionmentioning

confidence: 98%

Neurochemical phenotype of cytoglobin-expressing neurons in the rat hippocampus

2014

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Abstract. Cytoglobin (Cygb), a novel oxygen-binding protein, is expressed in the majority of tissues and has been proposed to function in nitric oxide (NO) metabolism in the vasculature and to have cytoprotective properties. However, the overall functions of Cygb remain elusive. Cygb is also expressed in a subpopulation of brain neurons. Recently, it has been shown that stress upregulates Cygb expression in the brain and the majority of neuronal nitric oxide synthase (nNOS)-positive neurons, an enzyme that produces NO, co-express Cygb. However, there are more neurons expressing Cygb than nNOS, thus a large number of Cygb neurons remain uncharacterized by the neurochemical content. The aim of the present study was to provide an additional and more detailed neurochemical phenotype of Cygb-expressing neurons in the rat hippocampus. The rat hippocampus was chosen due to the abundance of Cygb, as well as this limbic structure being an important target in a number of neurodegenerative diseases. Using triple immunohistochemistry, it was demonstrated that nearly all the parvalbumin-and heme oxygenase 1-positive neurons co-express Cygb and to a large extent, these neuron populations are distinct from the population of Cygb neurons co-expressing nNOS. Furthermore, it was shown that the majority of neurons expressing somastostatin and vasoactive intestinal peptide also co-express Cygb and nNOS. Detailed information regarding the neurochemical phenotype of Cygb neurons in the hippocampus can be a valuable tool in determining the function of Cygb in the brain.

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Section: Discussionmentioning

confidence: 98%

Neurochemical phenotype of cytoglobin-expressing neurons in the rat hippocampus

2014

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“…Silencing of CYGB in myoblasts is sufficient to induce apoptosis and potentiated the pro-apoptotic effects of hypoxia and oxidants 12 . Modulation of CYGB levels in neonatal rat brains through adenoviral delivery strategies also regulated caspase levels and activation in response to ischemia reperfusion 39 . Our results are reminiscent of the aforementioned study, as indicated by a strong association between the loss of CYGB and caspase-3 activation (Figure 4D).…”

Section: Discussionmentioning

confidence: 99%

The Hemoglobin Homolog Cytoglobin in Smooth Muscle Inhibits Apoptosis and Regulates Vascular Remodeling

Jourd’heuil

Reilly

et al. 2017

ATVB

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Objective The role of hemoglobin and myoglobin in the cardiovascular system is well established, yet other globins in this context are poorly characterized. Here, we examined the expression and function of cytoglobin (CYGB) during vascular injury. Approach and Results We characterized CYGB content in intact vessels and primary vascular smooth muscle (VSM) cells and used two different vascular injury models to examine the functional significance of CYGB in vivo. We found that CYGB was strongly expressed in medial arterial VSM and human veins. In vitro and in vivo studies indicated that CYGB was lost upon VSM cell de-differentiation. In the rat balloon angioplasty model, site-targeted delivery of adenovirus encoding shRNA specific for CYGB prevented its re-expression and decreased neointima formation. Similarly, four weeks after complete ligation of the left common carotid, Cygb knockout mice displayed little to no evidence of neointimal hyperplasia in contrast to their wild-type littermates. Mechanistic studies in the rat indicated that this was primarily associated with increased medial cell loss, TUNEL staining, and caspase-3 activation, all indicative of prolonged apoptosis. In vitro, CYGB could be re-expressed upon VSM stimulation with cytokines and hypoxia and loss of CYGB sensitized human and rat aortic VSM cells to apoptosis. This was reversed upon antioxidant treatment or NOS2 inhibition. Conclusions These results indicate that CYGB is expressed in vessels primarily in differentiated medial vascular smooth muscle cells where it regulates neointima formation and inhibits apoptosis after injury.

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“…The globin fold also enables the tissue hemoglobin to serve as either a facilitator of oxygen transport within a cell, a scavenger of nitric oxide, and/or an enzyme with peroxidase activity. Hemoproteins such as cytoglobin (CYGB) neuroglobin (Ngb) have been implicated in mediating neurorestorative responses in models of hypoxia-ischemia and spinal cord trauma [58–60]. Although LC-O3PUFAs may also prevent the degradation of these key proteins, the effects of dietary LC-O3PUFAs on this important family needs to be clarified and further characterized.…”

Section: Discussionmentioning

confidence: 99%

Neurorestorative Targets of Dietary Long-Chain Omega-3 Fatty Acids in Neurological Injury

Figueroa

León

2014

Mol Neurobiol

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Long-chain omega-3 polyunsaturated fatty acids (LC-O3PUFAs) exhibit therapeutic potential for the treatment and prevention of the neurological deficits associated with spinal cord injury (SCI). However, the mechanisms implicated in these protective responses remain unclear. The objective of the present functional metabolomics study was to identify and define the dominant metabolic pathways targeted by dietary LC-O3PUFAs. Sprague-Dawley rats were fed rodent purified chows containing menhaden fish oil-derived LC-O3PUFAs for 8 weeks before being subjected to sham or spinal cord contusion surgeries. We show, through untargeted metabolomics, that dietary LC-O3PUFAs regulate important biochemical signatures associated with amino acid metabolism and free radical scavenging in both the injured and sham-operated spinal cord. Of particular significance, the spinal cord metabolome of animals fed with LC-O3PUFAs exhibited reduced glucose levels (−48%) and polar uncharged/hydrophobic amino acids (<−20%) while showing significant increases in the levels of antioxidant/anti-inflammatory amino acids and peptides metabolites, including β-alanine (+24%), carnosine (+33%), homocarnosine (+27%), kynurenine (+88%), when compared to animals receiving control diets (p < 0.05). Further, we found that dietary LC-O3PUFAs impacted the levels of neurotransmitters and the mitochondrial metabolism, as evidenced by significant increases in the levels of N-acetylglutamate (+43%) and acetyl-CoA levels (+27%), respectively. Interestingly, this dietary intervention resulted in a global correction of the pro-oxidant metabolic profile that characterized the SCI-mediated sensorimotor dysfunction. In summary, the significant benefits of metabolic homeostasis and increased antioxidant defenses unlock important neurorestorative pathways of dietary LC-O3PUFAs against SCI.

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Mechanisms of Neuroprotection from Hypoxia-Ischemia (HI) Brain Injury by Up-regulation of Cytoglobin (CYGB) in a Neonatal Rat Model

Cited by 47 publications

References 80 publications

Neurochemical phenotype of cytoglobin-expressing neurons in the rat hippocampus

Neurochemical phenotype of cytoglobin-expressing neurons in the rat hippocampus

The Hemoglobin Homolog Cytoglobin in Smooth Muscle Inhibits Apoptosis and Regulates Vascular Remodeling

Neurorestorative Targets of Dietary Long-Chain Omega-3 Fatty Acids in Neurological Injury

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