MicroRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease.
Summary of "MicroRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease."
Although individuals with homozygous sickle cell disease (HbSS) share the same genetic mutation, the severity and manifestations of this disease are extremely heterogeneous. We have previously shown that the microRNA expression in HbAA and HbSS erythrocytes exhibit dramatic differences. In this study, we identify a subset of HbSS patients with higher erythrocytic miR-144 expression and more severe anemia. HbSS erythrocytes are known to have reduced tolerance for oxidative stress, yet the basis for this phenotype remains unknown. This study reveals that miR-144 directly regulates NRF2, a central regulator of cellular response to oxidative stress, and modulates the oxidative stress response in K562 cell line and primary erythroid progenitor cells. We further demonstrate that increased miR-144 is associated with reduced NRF2 levels in HbSS reticulocytes and with decreased glutathione regeneration and attenuated antioxidant capacity in HbSS erythrocytes, thereby providing a possible mechanism for the reduced oxidative stress tolerance and increased anemia severity seen in HbSS patients. Taken together, our findings suggest that erythroid microRNAs can serve as genetic modifiers of HbS-related anemia and can provide novel insights into the clinical heterogeneity and pathobiology of sickle cell disease.
The Institute for Genome Sciences and Policy, Duke University School of Medicine, Durham, NC, United States;
This article was published in the following journal.
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20709907
- DOI: http://dx.doi.org/10.1182/blood-2009-04-214817
Medical and Biotech [MESH] Definitions
A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi).
Fanconi Anemia Complementation Group Proteins
A diverse group of proteins whose genetic MUTATIONS have been associated with the chromosomal instability syndrome FANCONI ANEMIA. Many of these proteins play important roles in protecting CELLS against OXIDATIVE STRESS.
The appearance of carbonyl groups (such as aldehyde or ketone groups) in PROTEINS as the result of several oxidative modification reactions. It is a standard marker for OXIDATIVE STRESS. Carbonylated proteins tend to be more hydrophobic and resistant to proteolysis.
A direct-acting oxidative stress-inducing agent used to examine the effects of oxidant stress on Ca(2+)-dependent signal transduction in vascular endothelial cells. It is also used as a catalyst in polymerization reactions and to introduce peroxy groups into organic molecules.
Activating Transcription Factor 3
An activating transcription factor that plays a key role in cellular responses to GENOTOXIC STRESS and OXIDATIVE STRESS.
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