Document Detail


Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease.
MedLine Citation:
PMID:  23349388     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Chronic inflammation has emerged as an important pathogenic mechanism in sickle cell disease (SCD). One component of this inflammatory response is oxidant stress mediated by reactive oxygen species (ROS) generated by leukocytes, endothelial cells, plasma enzymes, and sickle red blood cells (RBC). Sickle RBC ROS generation has been attributed to sickle hemoglobin auto-oxidation and Fenton chemistry reactions catalyzed by denatured heme moieties bound to the RBC membrane. In this study, we demonstrate that a significant part of ROS production in sickle cells is mediated enzymatically by NADPH oxidase, which is regulated by protein kinase C, Rac GTPase, and intracellular Ca(2+) signaling within the sickle RBC. Moreover, plasma from patients with SCD and isolated cytokines, such as transforming growth factor β1 and endothelin-1, enhance RBC NADPH oxidase activity and increase ROS generation. ROS-mediated damage to RBC membrane components is known to contribute to erythrocyte rigidity and fragility in SCD. Erythrocyte ROS generation, hemolysis, vaso-occlusion, and the inflammatory response to tissue damage may therefore act in a positive-feedback loop to drive the pathophysiology of sickle cell disease. These findings suggest a novel pathogenic mechanism in SCD and may offer new therapeutic targets to counteract inflammation and RBC rigidity and fragility in SCD.
Authors:
Alex George; Suvarnamala Pushkaran; Diamantis G Konstantinidis; Sebastian Koochaki; Punam Malik; Narla Mohandas; Yi Zheng; Clinton H Joiner; Theodosia A Kalfa
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-01-24
Journal Detail:
Title:  Blood     Volume:  121     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-05-13     Revised Date:  2014-08-07    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2099-107     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Anemia, Sickle Cell / blood,  metabolism*,  pathology
Calcium / pharmacology
Cell Aging / drug effects,  physiology
Child
Cytokines / blood,  metabolism,  pharmacology*
Enzyme Activation / drug effects
Erythrocytes / enzymology*,  pathology,  physiology
Humans
Isoenzymes / metabolism
Models, Biological
NADPH Oxidase / metabolism,  physiology*
Oxidative Stress* / drug effects
Protein Kinase C / metabolism*
Reactive Oxygen Species / metabolism,  pharmacology
rac GTP-Binding Proteins / metabolism*
Grant Support
ID/Acronym/Agency:
DK26263/DK/NIDDK NIH HHS; K08 HL088126/HL/NHLBI NIH HHS; K08HL088126/HL/NHLBI NIH HHS; P30 DK090971/DK/NIDDK NIH HHS; P30DK090971/DK/NIDDK NIH HHS; R01 HL116352/HL/NHLBI NIH HHS; R01HL116352/HL/NHLBI NIH HHS; R37 DK026263/DK/NIDDK NIH HHS; U54HL070871/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Cytokines; 0/Isoenzymes; 0/Reactive Oxygen Species; EC 1.6.3.1/NADPH Oxidase; EC 2.7.11.13/Protein Kinase C; EC 3.6.5.2/rac GTP-Binding Proteins; SY7Q814VUP/Calcium
Comments/Corrections
Erratum In:
Blood. 2014 Mar 20;123(12):1972

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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