期刊
REDOX BIOLOGY
卷 32, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.redox.2020.101468
关键词
Cancer; Cardiovascular disease; Cytoglobin; Fibrosis; Hemoglobin; Hydrogen peroxide; Hypoxia; Myoglobin; Nitric oxide; Oxidative stress
资金
- American Heart Association [16GRNT31280002]
- National Institutes of Health [1RO1HL142807-01A1]
Cytoglobin is an evolutionary ancient hemoglobin with poor functional annotation. Rather than constrained to penta coordination, cytoglobin's heme iron may exist either as a penta or hexacoordinated arrangement when exposed to different intracellular environments. Two cysteine residues at the surface of the protein form an intramolecular disulfide bond that regulates iron coordination, ligand binding, and peroxidase activity. Overall, biochemical results do not support a role for cytoglobin as a direct antioxidant enzyme that scavenges hydrogen peroxide because the rate of the reaction of cytoglobin with hydrogen peroxide is several orders of magnitude slower than metal and thiol-based peroxidases. Thus, alternative substrates such as fatty acids have been suggested and regulation of nitric oxide bioavailability through nitric oxide dioxygenase and nitrite reductase activities has received experimental support. Cytoglobin is broadly expressed in connective, muscle, and nervous tissues. Rational for differential cellular distribution is poorly understood but inducibility in response to hypoxia is one of the most established features of cytoglobin expression with regulation through the transcription factor hypoxia-inducible factor (HIF). Phenotypic characterization of cytoglobin deletion in the mouse have indicated broad changes that include a heightened inflammatory response and fibrosis, increase tumor burden, cardiovascular dysfunction, and hallmarks of senescence. Some of these changes might be reversed upon inhibition of nitric oxide synthase. However, subcellular and molecular interactions have been seldom characterized. In addition, specific molecular mechanisms of action are still lacking. We speculate that cytoglobin functionality will extend beyond nitric oxide handling and will have to encompass indirect regulatory antioxidant and redox sensing functions.
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