Detrimental effects of adenosine signaling in sickle cell disease

Zhang, Yujin; Dai, Yingbo; Wen, Jiaming; Zhang, Weiru; Grenz, Almut; Sun, Hong; Tao, Ling; Lu, Guangxiu; Alexander, Danny; Milburn, Michael V.; Carter-Dawson, Louvenia; Lewis, Dorothy E.; Zhang, Wenzheng; Eltzschig, Holger K.; Kellems, Rodney E.; Blackburn, Michael R.; Juneja, Harinder S.; Xia, Yang

doi:10.1038/nm.2280

Cited by 174 publications

(239 citation statements)

References 41 publications

Supporting

Mentioning

226

Contrasting

Unclassified

Order By: Relevance

“…This signature was found to be composed of both novel and established PH candidate genes as evidenced by literature mining and the PubMed search tool. For example, ADORA2B, a candidate gene known to modify the severity of SCD (20,21), was recently identified via metabolomic profiling of a transgenic SCD mouse model with excessive adenosine signaling through the ADORA2B leading to sickling and hemolysis (22), processes known to be independently correlated with the presence of PH in SCD (13,23). Furthermore, ADC, another signature gene, which decarboxylates L-arginine to agmatine, is an established PAH candidate gene (24) and is potentially involved in SCD-related PH (25).…”

Section: Discussionmentioning

confidence: 99%

A Novel Molecular Signature for Elevated Tricuspid Regurgitation Velocity in Sickle Cell Disease

Desai¹,

Zhou²,

Ahmad

et al. 2012

Am J Respir Crit Care Med

View full text Add to dashboard Cite

Rationale: An increased tricuspid regurgitation jet velocity (TRV . 2.5 m/s) and pulmonary hypertension defined by right heart catheterization both independently confer increased mortality in sickle cell disease (SCD). Objectives: We explored the usefulness of peripheral blood mononuclear cell-derived gene signatures as biomarkers for an elevated TRV in SCD. Methods: Twenty-seven patients with SCD underwent echocardiography and peripheral blood mononuclear cell isolation for expression profiling and 112 patients with SCD were genotyped for single-nucleotide polymorphisms. Measurements and Main Results: Genome-wide gene and miRNA expression profiles were correlated against TRV, yielding 631 transcripts and 12 miRNAs. Support vector machine analysis identified a 10-gene signature including GALNT13 (encoding polypeptide N-acetylgalactosaminyltransferase 13) that discriminates patients with and without increased TRV with 100% accuracy. This finding was then validated in a cohort of patients with SCD without (n ¼ 10) and with pulmonary hypertension (n ¼ 10, 90% accuracy). Increased TRV-related miRNAs revealed strong in silico binding predictions of miR-301a to GALNT13 corroborated by microarray analyses demonstrating an inverse correlation between their expression. A genetic association study comparing patients with an elevated (n ¼ 49) versus normal (n ¼ 63) TRV revealed five significant single-nucleotide polymorphisms within GALNT13 (P , 0.005), four trans-acting (P , 2.1 3 10 27) and one cis-acting (P ¼ 0.6 3 10 24 ) expression quantitative trait locus upstream of the adenosine-A2B receptor gene (ADORA2B). Conclusions: These studies validate the clinical usefulness of genomic signatures as potential biomarkers and highlight ADORA2B and GALNT13 as potential candidate genes in SCD-associated elevated TRV.

show abstract

Section: Discussionmentioning

confidence: 99%

A Novel Molecular Signature for Elevated Tricuspid Regurgitation Velocity in Sickle Cell Disease

Desai¹,

Zhou²,

Ahmad

et al. 2012

Am J Respir Crit Care Med

View full text Add to dashboard Cite

show abstract

“…Besides the obvious sickleshaped cells, we considered the reversible sickle cells with sharp and pointed protrusions and deformed cells with aberrant morphologies as sickle cells. The percentage of sickle cells of the total RBCs was calculated (Zhang et al, 2011).…”

Section: Light Microscopymentioning

confidence: 99%

Visualizing red blood cell sickling and the effects of inhibition of sphingosine kinase 1 using soft X-ray tomography

Darrow

Zhang

Cinquin

et al. 2016

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

Sickle cell disease is a destructive genetic disorder characterized by the formation of fibrils of deoxygenated hemoglobin, leading to the red blood cell (RBC) morphology changes that underlie the clinical manifestations of this disease. Using cryogenic soft X-ray tomography (SXT), we characterized the morphology of sickled RBCs in terms of volume and the number of protrusions per cell. We were able to identify statistically a relationship between the number of protrusions and the volume of the cell, which is known to correlate to the severity of sickling. This structural polymorphism allows for the classification of the stages of the sickling process. Recent studies have shown that elevated sphingosine kinase 1 (Sphk1)-mediated sphingosine 1-phosphate production contributes to sickling. Here, we further demonstrate that compound 5C, an inhibitor of Sphk1, has anti-sickling properties. Additionally, the variation in cellular morphology upon treatment suggests that this drug acts to delay the sickling process. SXT is an effective tool that can be used to identify the morphology of the sickling process and assess the effectiveness of potential therapeutics.

show abstract

“…It has been reported that the activation of the adenosine A 2B receptor may increase the deleterious effects of SCD, promoting priapism and the sickling of erythrocytes [91]. Antagonists such as MS-1706 can reverse priapism [92].…”

Section: Inherited Hemoglobin Disordersmentioning

confidence: 99%

Sickle Cell Disease – Current Treatment and New Therapeutical Approaches

Melo¹,

Ercolin²,

Chelucci³

et al. 2015

Inherited Hemoglobin Disorders

View full text Add to dashboard Cite

Sickle cell disease (SCD) is one of the most common genetic disorders worldwide. It is caused by a point mutation that changes glutamic acid (Glu6) to valine (Val6) in the β chain of hemoglobin. Vaso-occlusion is the most well-known problem associated with SCD. Despite recent advances in understanding the disease at the molecular level, few therapeutic strategies are available. Hydroxyurea is the only drug currently approved by the U.S. Food and Drug Administration for the disease, and it has serious adverse effects and lack of efficacy in some patients. However, new therapeutic approaches are under investigation in the hope of discovering new drugs to treat SCD.These include agents that: a) increase nitric oxide bioavailability; b) modify the rheological properties of the blood; c) bind covalently to hemoglobin; d) prevent hemoglobin dehydration; e) reduce iron overload; and f) induce the expression of gamma globin and fetal hemoglobin. In this chapter, we discuss the current treatment of SCD and the advances made in medicinal chemistry to find new drugs to treat this neglected hematological disease.

show abstract

Detrimental effects of adenosine signaling in sickle cell disease

Cited by 174 publications

References 41 publications

A Novel Molecular Signature for Elevated Tricuspid Regurgitation Velocity in Sickle Cell Disease

A Novel Molecular Signature for Elevated Tricuspid Regurgitation Velocity in Sickle Cell Disease

Visualizing red blood cell sickling and the effects of inhibition of sphingosine kinase 1 using soft X-ray tomography

Sickle Cell Disease – Current Treatment and New Therapeutical Approaches

Contact Info

Product

Resources

About